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

Abstract

Objective: Individuals with the trinucleotide CAG expansion (CAG+) that causes Huntington's 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 MRI 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 presupplementary 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.

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. (PsycINFO Database Record (c) 2011 APA, all rights reserved).

Figure 1. The fMRI task protocol

A central circle turns green (G) for a PS (A) and red (R) for an AS (B) (panel 1). The circle is extinguished as a horizontal peripheral square (stimulus) appears. For a PS, participants look at the square; for an AS, participants look directly opposite the square (panel 2). The central circle then reappears (panel 3), upon which participants fixate while awaiting the next instruction. Dotted circle indicates the correct eye position (shown here for illustration purposes, but not visible to participants during testing). s: seconds.

Figure 2. Performance on the PS and AS tasks

For the PS task, the CAG− group made significantly fewer errors than the preHD and early HD group. For the AS task, the early HD group made significantly more errors than the CAG− and preHD groups. Error bars indicate standard error. AS: antisaccade; PS: prosaccade.

Figure 3. Functional ROIs defined in CAG− participants for each saccade comparison

(A) Significant activation during preparation for the [correct AS > correct PS] comparison in the bilateral DLPFC, FEF, PEF, and MOG; the right insula and calcarine cortex; and the pre-SMA/dACC. (B) Significant response-related activation for [correct AS > correct PS] in the right PEF. (C) Significant activation during preparation for the [incorrect AS > correct AS] comparison in the bilateral calcarine cortices. (D) Significant activation during responses for [incorrect AS > correct AS] in the left IFG, pre-SMA, dACC, PCC, right IPL, and left MTG. AS: antisaccade; dACC: dorsal anterior cingulate cortex; DLPFC: dorsolateral prefrontal cortex; FEF: frontal eye fields; IFG: inferior frontal gyrus; IPL: inferior parietal lobule; L: left; MOG: middle occipital gyrus; MTG: middle temporal gyrus; PCC: posterior cingulate cortex; PEF: parietal eye fields; pre-SMA: pre-supplementary motor area.

Figure 4. BOLD response as a function of the percentage of incorrect AS

In the pre-SMA (A) and dACC (B) [incorrect AS > correct AS] activation is dependent on the percentage of incorrect AS in the CAG− group but not in either CAG+ group; the CAG− group has greater overall activation. Furthermore, there are no differences in activation between the preHD and early HD groups. AS: antisaccade; BOLD: blood oxygenation level dependent; dACC: dorsal anterior cingulate cortex; DLPFC: dorsolateral prefrontal cortex; MOG: middle occipital gyrus; pre-SMA: pre-supplementary motor area; PS: prosaccade.

Figure 4. BOLD response as a function of the percentage of incorrect AS

In the pre-SMA (A) and dACC (B) [incorrect AS > correct AS] activation is dependent on the percentage of incorrect AS in the CAG− group but not in either CAG+ group; the CAG− group has greater overall activation. Furthermore, there are no differences in activation between the preHD and early HD groups. AS: antisaccade; BOLD: blood oxygenation level dependent; dACC: dorsal anterior cingulate cortex; DLPFC: dorsolateral prefrontal cortex; MOG: middle occipital gyrus; pre-SMA: pre-supplementary motor area; PS: prosaccade.