Functional magnetic resonance imaging of working memory in Huntington's disease: cross-sectional data from the IMAGE-HD study

Abstract

We used functional magnetic resonance imaging (fMRI) to investigate spatial working memory (WM) in an N-BACK task (0, 1, and 2-BACK) in premanifest Huntington's disease (pre-HD, n = 35), early symptomatic Huntington's disease (symp-HD, n = 23), and control (n = 32) individuals. Overall, both WM conditions (1-BACK and 2-BACK) activated a large network of regions throughout the brain, common to all groups. However, voxel-wise and time-course analyses revealed significant functional group differences, despite no significant behavioral performance differences. During 1-BACK, voxel-wise blood-oxygen-level-dependent (BOLD) signal activity was significantly reduced in a number of regions from the WM network (inferior frontal gyrus, anterior insula, caudate, putamen, and cerebellum) in pre-HD and symp-HD groups, compared with controls; however, time-course analysis of the BOLD response in the dorsolateral prefrontal cortex (DLPFC) showed increased activation in symp-HD, compared with pre-HD and controls. The pattern of reduced voxel-wise BOLD activity in pre-HD and symp-HD, relative to controls, became more pervasive during 2-BACK affecting the same structures as in 1-BACK, but also incorporated further WM regions (anterior cingulate gyrus, parietal lobe and thalamus). The DLPFC BOLD time-course for 2-BACK showed a reversed pattern to that observed in 1-BACK, with a significantly diminished signal in symp-HD, relative to pre-HD and controls. Our findings provide support for functional brain reorganisation in cortical and subcortical regions in both pre-HD and symp-HD, which are modulated by task difficulty. Moreover, the lack of a robust striatal BOLD signal in pre-HD may represent a very early signature of change observed up to 15 years prior to clinical diagnosis.

Keywords: DLPFC; Huntington's Disease; N BACK; fMRI; working memory.

Figure 1

Representation of the 0‐BACK, 1‐BACK and 2‐BACK conditions and their expected responses denoted by the arrow. Participants only view a single stimulus diamond at a time. 0‐BACK requires the participants to respond to the location of the number currently seen. 1‐BACK requires the participants to encode the position of the current stimulus and to respond to the number seen one stimulus back. 2‐BACK requires the participants to encode the position of the current stimulus and to respond to the number seen two stimuli back. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 2

Brain regions showing BOLD signal increase during the 1‐BACK condition in comparison to the 0‐BACK baseline condition. The main effects seen in controls (A), pre‐HD (B), and symp‐HD (C). Group differences are shown for controls versus pre‐HD (D) and controls versus symp‐HD (E). Axial slices are z = −6 to 44; sagittal slices are x = 44 (A–C), 12 (D), and 40 (E). Images are in 2 mm MNI space in radiological orientation (right hemisphere is at the left side of the image).

Figure 3

Brain regions showing BOLD signal increase during the 2‐BACK condition in comparison to the 0‐BACK baseline condition. The main effects seen in controls (A), pre‐HD (B), and symp‐HD (C). Group differences are shown for controls versus pre‐HD (D) and controls versus symp‐HD (E). Axial slices are z = −6 to 44; sagittal slices are x = 44 (A–C) and 8 (D), and 12 (E). Images are in 2 mm MNI space in radiological orientation (right hemisphere is at the left side of the image).

Figure 4

Time‐course graphs of ROIs showing significant group effects and Group by Time interactions during the 1‐BACK and 2‐BACK conditions in comparison to the 0‐BACK baseline condition. Shown are time‐courses for the dorsolateral prefrontal cortex (DLPFC), caudate, and putamen. A significant main effect of Group is indicated by a “+” sign on the top right corner of a plot; a Group by Time interaction is indicated by a “x” sign on the top right corner of a plot; pairwise differences between groups are represented by the letters a, b, and c next to the relevant time‐course: a, ΔPre‐HD versus Symp‐HD; b, ΔPre‐HD versus Controls; c, Δ Symp‐HD versus Controls; group differences at a specific point in the time‐course: *Δ Pre‐HD versus Controls; ∧Δ Symp‐HD versus Controls; ^oΔ Pre‐HD versus Symp‐HD. Significance for all tests is P < 0.05. Time‐courses are statistically compared starting at 0 sec. Images are in radiological orientation (right hemisphere is at the left side of the image).