Randomised, double-blind, placebo-controlled crossover study of single-dose guanfacine in unilateral neglect following stroke

OBJECTIVE: Unilateral neglect is a poststroke disorder that impacts negatively on functional outcome and lacks established, effective treatment. This multicomponent syndrome is characterised by a directional bias of attention away from contralesional space, together with impairments in several cognitive domains, including sustained attention and spatial working memory. This study aimed to test the effects of guanfacine, a noradrenergic alpha-2A agonist, on ameliorating aspects of neglect.METHODS: Thirteen right hemisphere stroke patients with leftward neglect were included in a randomised, double-blind, placebo-controlled proof-of-concept crossover study that examined the effects of a single dose of guanfacine. Patients were tested on a computerised, time-limited cancellation paradigm, as well as tasks that independently assessed sustained attention and spatial working memory.RESULTS: On guanfacine, there was a statistically significant improvement in the total number of targets found on the cancellation task when compared with placebo (mean improvement of 5, out of a possible 64). However, there was no evidence of a change in neglect patients' directional attention bias. Furthermore, Bayesian statistical analysis revealed reliable evidence against any effects of guanfacine on search organisation and performance on our sustained attention and spatial working memory tasks.CONCLUSIONS: Guanfacine improves search in neglect by boosting the number of targets found but had no effects on directional bias or search organisation, nor did it improve sustained attention or working memory on independent tasks. Further work is necessary to determine whether longer term treatment with guanfacine may be effective for some neglect patients and whether it affects functional outcome measures.TRIAL REGISTRATION NUMBER: NCT00955253.</p

Reward and dopaminergic modulation of attentional deficits in the neglect syndrome

Visuospatial neglect, most commonly associated with injury to the right cerebral hemisphere, is primarily a disorder of attention. Whilst at its core there undisputedly lies a spatially-lateralised bias, there is now wide acceptance that it also comprises non-spatial components, including deficits of selective and sustained attention. Furthermore, following reports of reward-related improvement in neglect, there is increasing evidence that motivational factors may be involved, which may be amenable to dopaminergic modulation. The experiments described here aim to examine the interaction between reward and the non-spatial components of the neglect syndrome, and to determine what influences dopamine has on the disorder and on the reward-attention interaction in neglect. The effect of anticipated monetary reward on the attentional blink (AB), an index of temporal selective visual attention, was assessed using a rapid serial visual presentation task. Whilst reward abolished the AB effect in healthy controls, it improved overall performance of stroke patients, which was more evident in patients whose neglect had recovered. Reward modulation of sustained attention, probed using a continuous performance task, was also apparent. The effects were much clearer in the control group compared to stroke patients, and the majority of stroke patients did not exhibit a reward-attention response. Finally, I investigated how dopaminergic stimulation affects reward and attention in neglect. Compared to placebo, a single dose of levodopa improved cancellation and working memory, and reward was again shown to modulate neglect. Levodopa appeared to induce a reward-attention interaction in those patients where this was previously absent, but conferred no advantage in those with a pre-existing motivational response. These results confirm that attentional deficits in the neglect syndrome are amenable to motivational and dopaminergic modulation. Furthermore, they shed light on the dynamics between reward-attention interactions and dopamine, increasing the understanding of how these might be harnessed for effective neglect rehabilitation.Open Acces

The Effects of Motivational Reward on the Pathological Attentional Blink following Right Hemisphere Stroke

Recent work has shown that attentional deficits following stroke can be modulated by motivational stimulation, particularly anticipated monetary reward. Here we examined the effects of anticipated reward on the pathological attentional blink (AB), an index of temporal selective attention, which is prolonged in patients with right hemisphere damage and a history of left neglect. We specifically compared the effects of reward versus feedback-without-reward on the AB in 17 patients. We found that the patients all manifested impaired performance compared to healthy controls and that reward modulated the pathological blink in the patient group, but only in the second experimental session. When the performance of patients whose neglect had recovered was compared with that of patients who had ongoing or persistent neglect, reward appeared to only influence the AB in the former. These results have implications for our understanding of motivation-attention interactions following right hemisphere stroke, and how they may impact upon recovery from spatial neglect

Reward sensitivity predicts dopaminergic response in spatial neglect

Available online 18 September 2018.It has recently been revealed that spatial neglect can be modulated by motivational factors including anticipated monetary reward. A number of dopaminergic agents have been evaluated as treatments for neglect, but the results have been mixed, with no clear anatomical or cognitive predictors of dopaminergic responsiveness. Given that the effects of incentive motivation are mediated by dopaminergic pathways that are variably damaged in stroke, we tested the hypothesis that the modulatory influences of reward and dopaminergic drugs on neglect are themselves related. We employed a single-dose, double-blind, crossover design to compare the effects of Co-careldopa and placebo on a modified visual cancellation task in patients with neglect secondary to right hemisphere stroke. Whilst confirming that reward improved visual search in this group, we showed that dopaminergic stimulation only enhances visual search in the absence of reward. When patients were divided into REWARD-RESPONDERs and REWARD-NON-RESPONDERs, we found an interaction, such that only REWARD-NONRESPONDERs showed a positive response to reward after receiving Co-careldopa, whereas REWARD-RESPONDERs were not influenced by drug. At a neuroanatomical level, responsiveness to incentive motivation was most associated with intact dorsal striatum. These findings suggest that dopaminergic modulation of neglect follows an ‘inverted U’ function, is dependent on integrity of the reward system, and can be measured as a behavioural response to anticipated reward.This study was directly supported by the NIHR Biomedical Research Centre at Imperial College London and a HEFCE Clinical Senior Lectureship Award to PM. D.S. acknowledges support from the Spanish Ministry of Economy and Competitiveness (MINECO), through the 'Severo Ochoa' Programme for Centres/Units of Excellence in R&D (SEV-2015-490) and project grants PSI2016-76443-P from MINECO and PI-2017-25 from the Basque Government

Highly porous Ti 4

Porous, flexible, reactive electrochemical membranes (REMs) for water purification were synthesized by a novel simultaneous electrospinning/electrospraying (E/E) technique, which produced a network of poly(sulfone) fibers and Ti4O7 particles as evidenced by scanning electron microscopy. Cyclic voltammetry indicated that the kinetics for water electrolysis reactions and the Fe(CN)(6)(4-/3-) redox couple were enhanced by Ti4O7 deposition using the E/E technique. Membrane filtration experiments using phenol as a model contaminant showed a 2.6-fold enhancement in the observed first-order rate constant for phenol oxidation (k(obs,phenol)) in filtration mode relative to cross-flow operation. Phenol oxidation in filtration mode was approaching the pore diffusion mass transfer limit, and was 6 to 8 times higher than measured in a previous study that utilized a ceramic Ti4O7 REM operated in filtration mode and is comparable to rate constants obtained with carbon nanotube flow-through reactors, which are among the highest reported in the literature to date. (c) 2015 American Institute of Chemical Engineers AIChE J, 62: 508-524, 201