Abnormal error-related antisaccade activation in premanifest and early manifest Huntington disease.

Abstract

Objective-Individuals with the trinucleotide CAG expansion (CAG+) that causes Huntington disease (HD) have impaired performance on antisaccade (AS) tasks that require directing gaze in the mirror opposite direction of visual targets. This study aimed to identify the neural substrates underlying altered antisaccadic performance.Method-Three groups of participants were recruited: 1) Imminent and early manifest HD (early HD, n=8); 2) premanifest (presymptomatic) CAG+ (preHD, n=10); and 3) CAG unexpanded (CAG−) controls (n=12). All participants completed a uniform study visit that included a neurological evaluation, neuropsychological battery, molecular testing, and functional magnetic resonance imaging during an AS task. The blood oxygenation level dependent (BOLD) response was obtained during saccade preparation and saccade execution for both correct and incorrect responses using regression analysis.Results-Significant group differences in BOLD response were observed when comparing incorrect AS to correct AS execution. Specifically, as the percentage of incorrect AS increased, BOLD responses in the CAG− group decreased progressively in a well-documented reward detection network that includes the pre-supplementary motor area and dorsal anterior cingulate cortex. In contrast, AS errors in the preHD and early HD groups lacked this relationship with BOLD signal in the error detection network, and BOLD responses to AS errors were smaller in the two CAG+ groups as compared with the CAG− group. Publisher's Disclaimer:The following manuscript is the final accepted manuscript. It has not been subjected to the final copyediting, fact-checking, and proofreading required for formal publication. It is not the definitive, publisher-authenticated version. The American Psychological Association and its Council of Editors disclaim any responsibility or liabilities for errors or omissions of this manuscript version, any version derived from this manuscript by NIH, or other third parties. The published version is available at www.apa.org/pubs/journals/NEU NIH Public Access Conclusions-These results are the first to suggest that abnormalities in an error-related response network may underlie early changes in AS eye movements in premanifest and early manifest HD.

Executive deficit in spinocerebellar ataxia type 2 is related to expanded CAG repeats: Evidence from antisaccadic eye movements

“…Antisaccade abnormalities have been documented for other polyglutamine diseases such as SCA1, SCA3 (Rivaud-Pechoux et al, 1998), SCA17 (Hubner et al, 2007) and Huntington Disease (Rupp et al, 2011), suggesting a special vulnerability to polyglutamine expansions of the cortical-subcortical networks underlying antisaccades, regardless of the specific expanded protein. Furthermore, for Huntington Disease, antisaccade abnormalities can be detected even some years before disease onset, being an early marker of disease onset in asymptomatic mutation carriers (Rupp et al, 2011).…”

“…Furthermore, for Huntington Disease, antisaccade abnormalities can be detected even some years before disease onset, being an early marker of disease onset in asymptomatic mutation carriers (Rupp et al, 2011). Whether antisaccade abnormalities appear before the cerebellar ataxia in SCA2 is currently being tested in a large cohort of Cuban asymptomatic ATXN2 mutation carriers.…”

Neuroimaging Biomarkers of Neurodegenerative Diseases and Dementia

“…22 fMRI studies of antisaccade eye movement have also shown altered brain activation in task-related regions. 320 Studies of resting-state connectivity have shown reduced DMN connectivity in the anterior prefrontal cortex, inferior parietal lobe, and posterior cingulate, as well as reduced connectivity between cortical motor regions and the striatum in pre-HD patients. 321,322 Functional connectivity during a working memory task was also shown to be altered in patients with pre-HD in regions of the prefrontal cortex, striatum, and frontoparietal regions.…”

Cognition and Eye Movements

“…This widespread activity also occurs in patients with Huntington disease, but with progression of disease and an increase in antisaccade errors, there is loss of activity in presupplementary and dorsal anterior cingulate regions (76). In these patients, particularly with antisaccade error, activity is more widespread, indicating compensatory activation of cortex not normally involved in error monitoring (76).…”