Striatal dopaminergic dysfunction at rest and during task performance in writer's cramp

Abstract

Writer's cramp is a task-specific focal hand dystonia characterized by involuntary excessive muscle contractions during writing. Although abnormal striatal dopamine receptor binding has been implicated in the pathophysiology of writer's cramp and other primary dystonias, endogenous dopamine release during task performance has not been previously investigated in writer's cramp. Using positron emission tomography imaging with the D2/D3 antagonist 11C-raclopride, we analysed striatal D2/D3 availability at rest and endogenous dopamine release during sequential finger tapping and speech production tasks in 15 patients with writer's cramp and 15 matched healthy control subjects. Compared with control subjects, patients had reduced 11C-raclopride binding to D2/D3 receptors at rest in the bilateral striatum, consistent with findings in previous studies. During the tapping task, patients had decreased dopamine release in the left striatum as assessed by reduced change in 11C-raclopride binding compared with control subjects. One cluster of reduced dopamine release in the left putamen during tapping overlapped with a region of reduced 11C-raclopride binding to D2/D3 receptors at rest. During the sentence production task, patients showed increased dopamine release in the left striatum. No overlap between altered dopamine release during speech production and reduced 11C-raclopride binding to D2/D3 receptors at rest was seen. Striatal regions where D2/D3 availability at rest positively correlated with disease duration were lateral and non-overlapping with striatal regions showing reduced D2/D3 receptor availability, except for a cluster in the left nucleus accumbens, which showed a negative correlation with disease duration and overlapped with striatal regions showing reduced D2/D3 availability. Our findings suggest that patients with writer's cramp may have divergent responses in striatal dopamine release during an asymptomatic motor task involving the dystonic hand and an unrelated asymptomatic task, sentence production. Our voxel-based results also suggest that writer's cramp may be associated with reduced striatal dopamine release occuring in the setting of reduced D2/D3 receptor availability and raise the possibility that basal ganglia circuits associated with premotor cortices and those associated with primary motor cortex are differentially affected in primary focal dystonias.

Keywords: PET; dopamine; dystonia; raclopride; striatum.

Figure 1

Experimental design for PET scans with ¹¹C-raclopride (RAC) using a bolus-plus-infusion design to assess D₂/D₃ receptor availability at rest and endogenous striatal dopamine release as measured by displacement of ¹¹C-RAC during sequential finger tapping and speech production tasks.

Figure 2

Statistical parametric maps showing ¹¹C-raclopride binding potential to striatal dopamine receptors (D₂/D₃) at rest in (A) healthy control subjects (HC) and (B) patients with writer’s cramp (WC). A contrast analysis (C) showed patients with writer’s cramp had a significant reduction in D₂/D₃ binding in the bilateral striatum. Colour bars show range of t-values displayed. Images are shown at P < 0.05, FWE corrected, on coronal slices of a standard brain in Talairach space.

Figure 3

Statistical parametric maps showing endogenous dopamine release as measured by displacement of ¹¹C-raclopride (RAC ΔBP) during a right-hand finger tapping task in (A) healthy control subjects (HC), (B) patients with writer’s cramp (WC), and (C) patients with writer’s cramp compared with healthy control subjects. (D) Left striatal regions showing decreased ¹¹C-RAC ΔBP during the tapping task (green) and striatal regions found to have reduced D₂/D₃ receptor availability at rest (yellow) showed one cluster of overlap in the left putamen (red). Colour bars show range of t-values displayed. Images are shown at P < 0.05, FWE corrected, on axial and coronal slices of a standard brain in Talairach space.

Figure 4

Statistical parametric maps showing endogenous dopamine release as measured by displacement of ¹¹C-raclopride (RAC ΔBP) during a speech production task in (A) healthy control subjects (HC) and (B) patients with writer’s cramp (WC), and (C) patients with writer’s cramp compared with healthy control subjects. Colour bars show range of t-values displayed. (D) Left striatal regions showing decreased ¹¹C-RAC ΔBP during the speech production task (green) were non-overlapping with striatal regions found to have reduced D₂/D₃ receptor availability at rest (yellow). Images are shown P < 0.05, FWE corrected, on axial and coronal slices of a standard brain in Talairach space.

Figure 5

Differences in ¹¹C-raclopride binding potential (RAC BP) to striatal dopamine receptors (D₂/D₃) during rest in healthy control subjects (HC) and patients with writer’s cramp (WC) generated using (A) atlas-defined whole putamen and caudate volumes of interest and (B) clusters defined by those striatal regions found to be significantly different between healthy control subjects and writer’s cramp in the voxel-based analyses. Also shown are bar graphs showing dopamine release as measured by displacement of ¹¹C-raclopride (¹¹C-RAC ΔBP) during (C) right-hand finger tapping and (D) speech production tasks in healthy control subjects and patients with writer’s cramp using clusters within the striatum found to be significantly different between healthy control subjects and writer’s cramp in the voxel-based analyses. Significant differences were evaluated using t-test comparisons (*P < 0.05; **P < 0.005; t: P < 0.1). Error bars reflect standard error of the mean. Lt = left; Rt = right.

Figure 6

(A) Voxel-wise correlation analysis between D₂/D₃ receptor availability at rest in patients with writer’s cramp (WC) as measured by ¹¹C-raclopride binding potential (RAC BP) and disease duration. Images are shown at a voxel threshold of P ≤ 0.025 (r = ± 0.60) with a cluster size threshold = 100, on axial and coronal slices of a standard brain in Talairach space. Colour bar shows range of r-values displayed. (B) Striatal regions showing a significant positive correlation between D₂/D₃ receptor availability at rest and disease duration (green) were non-overlapping and lateral to striatal regions found to have significantly reduced D₂/D₃ receptor availability at rest (yellow) compared to control subjects. One region of overlap (red) between these images was found in the left nucleus accumbens. (C) Scatterplots of disease duration and ¹¹C-RAC binding potential to striatal dopamine D₂/D₃ receptors during rest generated using bilateral striatal and left nucleus accumbens clusters found to be significantly different between healthy control subjects and writer’s cramp in the voxel-based analyses.