The effects of the dopamine agonist rotigotine on hemispatial neglect following stroke

Abstract

Hemispatial neglect following right-hemisphere stroke is a common and disabling disorder, for which there is currently no effective pharmacological treatment. Dopamine agonists have been shown to play a role in selective attention and working memory, two core cognitive components of neglect. Here, we investigated whether the dopamine agonist rotigotine would have a beneficial effect on hemispatial neglect in stroke patients. A double-blind, randomized, placebo-controlled ABA design was used, in which each patient was assessed for 20 testing sessions, in three phases: pretreatment (Phase A1), on transdermal rotigotine for 7-11 days (Phase B) and post-treatment (Phase A2), with the exact duration of each phase randomized within limits. Outcome measures included performance on cancellation (visual search), line bisection, visual working memory, selective attention and sustained attention tasks, as well as measures of motor control. Sixteen right-hemisphere stroke patients were recruited, all of whom completed the trial. Performance on the Mesulam shape cancellation task improved significantly while on rotigotine, with the number of targets found on the left side increasing by 12.8% (P = 0.012) on treatment and spatial bias reducing by 8.1% (P = 0.016). This improvement in visual search was associated with an enhancement in selective attention but not on our measures of working memory or sustained attention. The positive effect of rotigotine on visual search was not associated with the degree of preservation of prefrontal cortex and occurred even in patients with significant prefrontal involvement. Rotigotine was not associated with any significant improvement in motor performance. This proof-of-concept study suggests a beneficial role of dopaminergic modulation on visual search and selective attention in patients with hemispatial neglect following stroke.

Figure 1

Randomization of treatment allocation and permutation tests. (A) Randomization profile for a single patient. In this case, the treatment phase with rotigotine (Phase B, denoted in red) started on Day 7, and its duration was randomized to 8 days. Therefore, the patient participated in six baseline assessments (Phase A1, Sessions 1–6) and six follow-up sessions after discontinuation of rotigotine (Phase A2, Sessions 15–20). Placebo patch sessions are denoted in orange while sessions without any patches are shown in yellow. The actual difference in performance between treatment (Phase B) and the OFF treatment phases (A1 and A2) was ranked against the differences between phases produced by all other possible combinations of treatment allocation, given the limits in phase onset and duration. (B) All the possible permutations of pretreatment (Phase A1), treatment (Phase B) and post-treatment phase (Phase A2).

Figure 2

Lesion overlap maps. Axial MRI slices of stroke lesions in (A) the entire group of all 16 patients, (B) the minimal prefrontal involvement subgroup (eight patients) and (C) the extensive prefrontal involvement subgroup (eight patients). Colour values represent the number of patients in whom a given voxel was lesioned; note the scale is different for the entire group (A) compared with the subgroups (B and C).

Figure 3

Difference in performance on the Mesulam cancellation task ON and OFF rotigotine for all patients. A heatmap of the difference in targets found ON and OFF treatment for the entire patient group is overlaid on a Mesulam test sheet. Colour represents difference ON and OFF treatment in the number of targets found per session per patient at each target location. Treatment with rotigotine was associated with a significant increase in the number of targets identified on the left side. A decrease in the number of targets found during treatment in a smaller area on the right-hand side was not statistically significant.

Figure 4

Overall effect of rotigotine treatment on Mesulam cancellation task. Y-axes represent per cent difference between performance ON treatment (Phase B) and OFF treatment (average of Phases A1 and A2), relative to OFF treatment baseline. The actual differences ON and OFF treatment (in red) are compared with the average (±average SEM) of differences between Phases B and the average of A1 and A2 produced by all possible combinations of the data (in grey). *P < 0.05. (A) The difference ON and OFF treatment in the number of targets found on the left side relative to baseline was higher in the actual treatment allocation, compared with all other possible permutations. (B) There was significantly less rightward bias in the location of the targets found during treatment with rotigotine, in comparison to differences produced by all possible permutations of the data.

Figure 5

Difference in Mesulam task performance ON and OFF rotigotine in the two subgroups defined according to involvement of prefrontal cortex in the stroke lesion. (A) In the subgroup with minimal prefrontal involvement, the number of targets found on the left side increased significantly on treatment. (B) Patients with extensive prefrontal involvement showed a significant reduction in rightward spatial bias during treatment.

Figure 6

Mesulam task performance ON and OFF rotigotine in individual patients. Response to rotigotine was variable, across patients (presented in the same order as in Table 1). (A) Difference in left targets found ON versus OFF treatment. Red circles represent the actual difference in performance ON and OFF rotigotine for each individual. Grey squares denote the mean difference derived from all possible permutations of the data while the error bars show the range of values of such means for all possible permutations. Red circles situated on the right of error bars signify a greater number of targets found while ON the drug when compared with all possible allocations of treatment and placebo. (B) Difference in spatial bias ON versus OFF treatment. Here leftward shifts in search are displayed in the left. Red circles on the left of error bars signify less rightward bias in the location of the targets found while on the drug when compared with all possible allocations of treatment and placebo. (C) Difference in number of targets found on left as a function of number of targets found OFF treatment. Improvements occurred both in patients with poor performance at baseline (small number of targets found on the left side) and in those with good baseline performance.

Figure 7

(A) Selective and sustained attention task. Participants detected targets (inverted triangles) among sequences of distractors (upright triangles) randomly presented to the ipsilesional and contralesional visual fields. Targets could be of the same colour as the distractors (red—low visual salience) or of a different colour (green—high visual salience). Participants were asked to respond with a button press as soon as they saw a target of any type. (B) Effect of rotigotine treatment on selective attention for left-sided targets. Y-axes represent per cent difference between performance ON (Phase B) and pretreatment (Phase A1), relative to pretreatment baseline. The actual differences ON and pretreatment (in red) are compared with the average (±average SEM) of difference between Phases B and A1 produced by all possible combinations of the data (in grey). The difference ON and pretreatment in the ratio of the reaction time (RT) to salient targets over non-salient targets on the left side relative to baseline was higher in the actual treatment allocation, when compared with all possible permutations. *P = 0.03. ISI = inter-stimulus interval.