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1.  Lower irritation microemulsion-based rotigotine gel: formulation optimization and in vitro and in vivo studies 
Rotigotine is a potent and selective D1, D2, and D3 dopaminergic receptor agonist. Due to an extensive first-pass effect, it has a very low oral bioavailability (approximately 0.5% in rats).
The present investigation aimed to develop a microemulsion-based hydrogel for transdermal rotigotine delivery with lower application site reactions.
Pseudoternary phase diagrams were constructed to determine the region of oil in water (o/w)-type microemulsion. Central composite design was used to support the pseudoternary phase diagrams and to select homogeneous and stable microemulsions with an optimal amount of rotigotine permeation within 24 hours. In vitro skin permeation experiments were performed, using Franz diffusion cells, to compare rotigotine-loaded microemulsions with rotigotine solutions in oil. The optimized formulation was used to prepare a microemulsion-based hydrogel, which was subjected to bioavailability and skin irritancy studies.
The selected formulations of rotigotine-loaded microemulsions had enhanced flux and permeation coefficients compared with rotigotine in oil. The optimum microemulsion contained 68% water, 6.8% Labrafil®, 13.44% Cremophor® RH40, 6.72% Labrasol®, and 5.04% Transcutol® HP; the drug-loading rate was 2%. To form a microemulsion gel, 1% Carbomer 1342 was added to the microemulsion. The bioavailability of the rotigotine-loaded microemulsion gel was 105.76%±20.52% with respect to the marketed rotigotine patch (Neupro®). The microemulsion gel irritated the skin less than Neupro.
A rotigotine microemulsion-based hydrogel was successfully developed, and an optimal formulation for drug delivery was identified. This product could improve patient compliance and have broad marketability.
PMCID: PMC4298334  PMID: 25609965
pseudoternary phase diagrams; central composite design; transdermal
2.  “Left Neglected,” but Only in Far Space: Spatial Biases in Healthy Participants Revealed in a Visually Guided Grasping Task 
Hemispatial neglect is a common outcome of stroke that is characterized by the inability to orient toward, and attend to stimuli in contralesional space. It is established that hemispatial neglect has a perceptual component, however, the presence and severity of motor impairments is controversial. Establishing the nature of space use and spatial biases during visually guided actions amongst healthy individuals is critical to understanding the presence of visuomotor deficits in patients with neglect. Accordingly, three experiments were conducted to investigate the effect of object spatial location on patterns of grasping. Experiment 1 required right-handed participants to reach and grasp for blocks in order to construct 3D models. The blocks were scattered on a tabletop divided into equal size quadrants: left near, left far, right near, and right far. Identical sets of building blocks were available in each quadrant. Space use was dynamic, with participants initially grasping blocks from right near space and tending to “neglect” left far space until the final stages of the task. Experiment 2 repeated the protocol with left-handed participants. Remarkably, left-handed participants displayed a similar pattern of space use to right-handed participants. In Experiment 3 eye movements were examined to investigate whether “neglect” for grasping in left far reachable space had its origins in attentional biases. It was found that patterns of eye movements mirrored patterns of reach-to-grasp movements. We conclude that there are spatial biases during visually guided grasping, specifically, a tendency to neglect left far reachable space, and that this “neglect” is attentional in origin. The results raise the possibility that visuomotor impairments reported among patients with right hemisphere lesions when working in contralesional space may result in part from this inherent tendency to “neglect” left far space irrespective of the presence of unilateral visuospatial neglect.
PMCID: PMC3898521  PMID: 24478751
pseudoneglect; visuospatial neglect; attention; human; peripersonal space; reach-to-grasp; handedness
3.  Effects of contralesional robot-assisted hand training in patients with unilateral spatial neglect following stroke: a case series study 
A reduction of hemispatial neglect due to stroke has been associated with activation of the contralesional hand in the contralesional hemispace. Robot-assisted upper limb training was found to effectively improve paretic arm function in stroke patients. To date no proof of concept of robot-assisted hemispatial neglect therapy has been reported in literature. This study aimed to determine whether robot-assisted left (contralesional) hand activation alone could lead to an improvement in hemispatial neglect following stroke.
Three stroke patients with right brain injury underwent a 2-week training program of robotic left hand activation with the Gloreha® hand rehabilitation glove, which provides repetitive, passive mobilization of the fingers. Outcomes were assessed using the Line Crossing test, the Bells test, the Sentence Reading test, the Saccadic Training, the Sustained Attention to Response Task, and the Purdue Pegboard test.
Changes were observed after treatment as follows. Line Crossing test: all patients showed improved performance (6.7%, 89.5% and 80% increase in lines crossed) with two patients reaching normal performance levels. Bells test: one patient improved performance (50% increase), while one patient showed no change and one patient declined (−10.3% change); no patient reached normal performance levels. Sentence Reading test: all patients showed improved performance (800%, 57.1% and 42.9% increase in number of sentences read) with no patient reaching normal performance level. Saccadic Training: all patients showed improved performance (−62.8%, −15.5% and −9.7% change of the left hemifield reaction time). Sustained Attention to Response Task: all patients showed improved performance (−20.5%, −5.8% and −10% change of the reaction time) with two patients reducing incorrect responses (−42.9% and −73.3%) and one patient increasing them (9.1%). Purdue Pegboard test: all patients showed improved performance (100%, 27.3% and 75% change in the left + right + both hands sub-item score).
Some caution is warranted when interpreting our results, as the responses to the intervention were variable and might have been due to a placebo effect or fluctuating clinical conditions. However, robot-assisted hemispatial neglect therapy might be useful in stroke patients. Larger-scale investigations are needed to confirm our preliminary findings.
PMCID: PMC4271413  PMID: 25476507
Rehabilitation; Perceptual disorders; Upper extremity
4.  Pharmacokinetics, Safety and Tolerability of Rotigotine Transdermal Patch in Healthy Japanese and Caucasian Subjects 
Clinical Drug Investigation  2013;34(2):95-105.
Background and Objectives
Rotigotine is a dopamine receptor agonist with activity across the D1 through to D5 receptors as well as select serotonergic and adrenergic sites; continuous transdermal delivery of rotigotine with replacement of the patch once daily maintains stable plasma concentrations over 24 h. Rotigotine is indicated for the treatment of early and advanced-stage Parkinson’s disease and moderate-to-severe idiopathic restless legs syndrome. The pharmacokinetics and pharmacodynamics of a drug may vary between subjects of different ethnic origin. This study evaluated the pharmacokinetics, safety, and tolerability of single-dose treatment with rotigotine transdermal patch in Japanese and Caucasian subjects.
In this open-label, parallel-group study, healthy male and female subjects of Japanese or Caucasian ethnic origin were matched by sex, body mass index, and age. A single transdermal patch delivering 2 mg/24 h rotigotine (patch content 4.5 mg) was applied to the ventral/lateral abdomen for 24 h. The main outcome measures were the plasma concentrations of unconjugated and total rotigotine and its desalkyl metabolites and derived pharmacokinetic parameters (area under the concentration–time curve from time zero to last quantifiable concentration [AUClast], maximum plasma concentration [Cmax], and body weight- and dose-normalized values).
The pharmacokinetic analysis included 48 subjects (24 Japanese, 24 Caucasian). The mean apparent dose of rotigotine was 2.0 ± 0.5 mg for Japanese subjects and 2.08 ± 0.58 mg for Caucasians. Plasma concentration–time profiles of unconjugated rotigotine and of the main metabolites were similar for both ethnic groups. Parameters of model-independent pharmacokinetics, Cmax, time to Cmax (tmax), and AUClast, for unconjugated rotigotine showed no statistically significant differences between Japanese and Caucasian subjects. Values of concentration-dependent pharmacokinetic parameters were higher in female subjects; this difference was minimized after correction for body weight. A statistically significant difference between ethnic groups was observed for total rotigotine concentrations (total rotigotine = unconjugated rotigotine + conjugated rotigotine), with slightly lower values in Caucasians after correction for body weight and apparent dose. No relevant differences were observed between males and females. Inter-individual variability was high. The terminal half-life for unconjugated rotigotine was 5.3 h in Japanese subjects and 5.7 h in Caucasians; corresponding values for total rotigotine were 8.6 h and 9.6 h. Less than 0.1 % of the apparent dose was renally excreted as the parent compound. Renal elimination of total rotigotine covers 11.7 % of absorbed dose in Japanese subjects and 10.8 % of the absorbed dose in Caucasians, whereas the renal elimination via total despropyl rotigotine was 8.2 and 7.1 %, respectively. The corresponding values for total desthienylethyl rotigotine were 3.5 % in Japanese subjects and 4.2 % Caucasians. Most adverse events were mild in intensity and typical for dopamine agonists or for transdermal therapeutics.
Administration of a single patch delivering 2 mg/24 h rotigotine resulted in comparable pharmacokinetic profiles in Japanese and Caucasian subjects. The rotigotine transdermal patch was generally well-tolerated. Our findings suggest similar dose requirements for Japanese and Caucasian populations.
PMCID: PMC3899448  PMID: 24178238
5.  Treatment of moderate to severe restless legs syndrome: 2-year safety and efficacy of rotigotine transdermal patch 
BMC Neurology  2010;10:86.
Rotigotine is a unique dopamine agonist with activity across D1 through D5 receptors as well as select adrenergic and serotonergic sites. This study reports the 2-year follow-up safety and efficacy data of an ongoing open-label multicenter extension study (NCT00498186) of transdermal rotigotine in patients with moderate to severe restless legs syndrome (RLS).
Patients received a once-daily patch application of an individually optimized dose of rotigotine between 0.5 mg/24 h to 4 mg/24 h. Safety assessments included adverse events (AEs) and efficacy was measured by the International RLS Study Group Severity Rating Scale (IRLS), RLS-6 scales and Clinical Global Impression (CGI). Quality of life (QoL) was measured by QoL-RLS.
Of 310 patients who completed a 6-week placebo-controlled trial (SP709), 295 (mean age 58 ± 10 years, 66% females) were included in the open-label trial SP710. 64.7% (190/295 patients) completed the 2-year follow-up; 29 patients discontinued during the second year. Mean daily rotigotine dose after 2 years was 2.93 ± 1.14 mg/24 h with a 2.9% dose increase from year 1. Rotigotine was generally well tolerated. The rate of typical dopaminergic side effects, nausea and fatigue, was low (0.9% and 2.3%, respectively) during the second year; application site reactions were frequent but lower than in year 1 (16.4% vs. 34.5%). The IRLS total score improved from baseline of SP709 (27.8 ± 5.9) by 17.2 ± 9.2 in year 2 completers. Similar improvements were observed in RLS-6 scales, CGI scores and QoL-RLS. The responder rate in the CGI change item 2 ("much" and "very much" improved) was 95% after year 2.
Transdermal rotigotine is an efficacious and well-tolerated long-term treatment option for patients with moderate to severe RLS with a high retention rate during 2 years of therapy.
Trial registration
PMCID: PMC2958158  PMID: 20920156
6.  Role of right posterior parietal cortex in maintaining attention to spatial locations over time 
Brain  2009;132(3):645-660.
Recent models of human posterior parietal cortex (PPC) have variously emphasized its role in spatial perception, visuomotor control or directing attention. However, neuroimaging and lesion studies also suggest that the right PPC might play a special role in maintaining an alert state. Previously, assessments of right-hemisphere patients with hemispatial neglect have revealed significant overall deficits on vigilance tasks, but to date there has been no demonstration of a deterioration of performance over time—a vigilance decrement—considered by some to be a key index of a deficit in maintaining attention. Moreover, sustained attention deficits in neglect have not specifically been related to PPC lesions, and it remains unclear whether they interact with spatial impairments in this syndrome. Here we examined the ability of right-hemisphere patients with neglect to maintain attention, comparing them to stroke controls and healthy individuals. We found evidence of an overall deficit in sustaining attention associated with PPC lesions, even for a simple detection task with stimuli presented centrally. In a second experiment, we demonstrated a vigilance decrement in neglect patients specifically only when they were required to maintain attention to spatial locations, but not verbal material. Lesioned voxels in the right PPC spanning a region between the intraparietal sulcus and inferior parietal lobe were significantly associated with this deficit. Finally, we compared performance on a task that required attention to be maintained either to visual patterns or spatial locations, matched for task difficulty. Again, we found a vigilance decrement but only when attention had to be maintained on spatial information. We conclude that sustaining attention to spatial locations is a critical function of the human right PPC which needs to be incorporated into models of normal parietal function as well as those of the clinical syndrome of hemispatial neglect.
PMCID: PMC2664449  PMID: 19158107
sustained attention; vigilance; neglect; attention; spatial memory
7.  Dynamic Spatial Coding within the Dorsal Frontoparietal Network during a Visual Search Task 
PLoS ONE  2008;3(9):e3167.
To what extent are the left and right visual hemifields spatially coded in the dorsal frontoparietal attention network? In many experiments with neglect patients, the left hemisphere shows a contralateral hemifield preference, whereas the right hemisphere represents both hemifields. This pattern of spatial coding is often used to explain the right-hemispheric dominance of lesions causing hemispatial neglect. However, pathophysiological mechanisms of hemispatial neglect are controversial because recent experiments on healthy subjects produced conflicting results regarding the spatial coding of visual hemifields. We used an fMRI paradigm that allowed us to distinguish two attentional subprocesses during a visual search task. Either within the left or right hemifield subjects first attended to stationary locations (spatial orienting) and then shifted their attentional focus to search for a target line. Dynamic changes in spatial coding of the left and right hemifields were observed within subregions of the dorsal front-parietal network: During stationary spatial orienting, we found the well-known spatial pattern described above, with a bilateral hemifield representation in the right hemisphere and a contralateral preference in the left hemisphere. However, during search, the right hemisphere had a contralateral preference and the left hemisphere equally represented both hemifields. This finding leads to novel perspectives regarding models of visuospatial attention and hemispatial neglect.
PMCID: PMC2525817  PMID: 18779857
8.  Dissociation of sensory-attentional from motor-intentional neglect 
OBJECTIVES—Spatial neglect may result from disruption of sensory-attentional systems that spatially allocate perceptual resources and the motor-intentional systems that direct exploration and action. Previous studies have suggested that the line bisection task is more sensitive to sensory-attentional disorders and the cancellation task to motor-intentional disorders. A new technique was developed that allows the dissociation of sensory-attentional and motor-intentional deficits in both tasks and thereby allows comparison of these tasks.
METHODS—Ten patients with right hemispheric injury and hemispatial neglect performed line bisection and cancellation tasks while viewing stimuli on closed circuit TV. Direct view of the exploring hand and the target was precluded; the TV monitor guided performance. The direct condition made the direction of hand movement on the table (workspace) congruent with that on the monitor. Inverting the camera produced the indirect condition wherein the lateral movement in the workspace occurred in the opposite direction on the monitor.
RESULTS—On the cancellation task, five patients marked targets in the right workspace in the direct condition but the left workspace in the indirect condition, indicating sensory-attentional neglect. However, four other patients cancelled targets only in the right workspace in both conditions, failing to explore the left workspace, suggesting motor-intentional neglect. A patient who performed ambiguously may have elements of both types of neglect. Only two out of five patients designated as sensory-attentional in cancellation tasks showed sensory neglect on line bisection. The other three patients, as well as patients defined as motor-intentional by cancellation performance, exhibited motor-intentional neglect on line bisection.
CONCLUSION—The designation of sensory-attentional versus motor-intentional neglect therefore, in part, depends on task specific demands.

PMCID: PMC2170001  PMID: 9527144
9.  Nonergot dopamine-receptor agonists for treating Parkinson’s disease – a network meta-analysis 
To compare the efficacy of the three nonergot dopamine-receptor agonists (DAs) pramipexole, ropinirole, and rotigotine for the treatment of early and advanced Parkinson’s disease (PD).
Materials and methods
Bayesian network meta-analyses were performed separately for early and advanced PD, and at time points 11–16 and 24–28 weeks. Outcomes for early PD included improvement on the Unified Parkinson’s Disease Rating Scale (UPDRS) activities in daily life (UPDRS-II), motor function (UPDRS-III), and their subtotal (UPDRS-II + III). Outcomes for advanced PD also included daily “off time” (hours), but not UPDRS-II + III.
Totals of 23 and 24 trials informed early and advanced PD analyses. For early PD UPDRS-II at 11–16 weeks, pramipexole and rotigotine were statistically significantly superior to placebo, but ropinirole was not. For UPDRS-III and UPDRS-II + III, all DAs were statistically significantly better than placebo and exhibited similar improvements. At 24–28 weeks, results were also statistically significant for all DAs versus placebo, and the magnitudes of improvements were similar for pramipexole, ropinirole and rotigotine. Advanced PD improvements on UPDRS-II, UPRDS-III, and off time were statistically significant for pramipexole, ropinirole, and rotigotine versus placebo. At 11–16 weeks, rotigotine yielded slightly smaller effects than ropinirole and pramipexole, but credible intervals on differences were wide. For off time, results were near identical. At 24–28 weeks, results were similar for all three outcomes. Ropinirole yielded a slightly higher improvement on UPDRS-III, but a slightly smaller improvement in off time.
Our analyses suggest that pramipexole, ropinirole, and rotigotine exhibit similar efficacy in the treatment of early and advanced PD.
PMCID: PMC4019622  PMID: 24855362
Parkinson’s disease; dopamine-receptor agonists; network meta-analysis
10.  Restless legs syndrome: differential diagnosis and management with rotigotine 
RLS is a common sleep disorder with distinctive clinical features. The prevalence of RLS in Caucasians and North Americans ranges from 5% to 10%. However, only some of these subjects (almost the 3% of the general population) report being affected by a frequent and severe form of the sleep disorder. RLS is diagnosed clinically by means of four internationally recognized criteria that summarize the main characteristics of the sleep disorder. Besides the essential criteria, supportive and associated features of RLS have been established by experts in order to help physicians treat patients with doubtful symptoms. Several clinical conditions may mimic this sleep disorder. In order to increase the sensibility and specificity of RLS diagnosis, doctors should perform a meticulous patient history and then an accurate physical and neurological examination. Dopamine agonists are recognized as the preferred first-line treatment for RLS. Rotigotine is a non-ergoline dopamine agonist with selectivity for D1, D2 and D3 receptors. The drug is administered via transdermal patches which release rotigotine for 24 hours. Four clinical trials demonstrated that this compound is able to improve RLS symptomatology with few and moderate adverse events. Head to head trials are required to compare the efficacy and tolerability of rotigotine with other dopamine agonists administered via oral intake. Rotigotine has been approved by the FDA and EMEA for Parkinson’s disease. For the treatment of moderate to severe idiopathic RLS, rotigotine has been recommended for approval by the EMEA and is under review by the FDA.
PMCID: PMC2695234  PMID: 19557102
restless legs syndrome; diagnosis; differential diagnosis; dopamine agonists; rotigotine
11.  Reducing Chronic Visuo-Spatial Neglect Following Right Hemisphere Stroke Through Instrument Playing 
Unilateral visuo-spatial neglect is a neuropsychological syndrome commonly resulting from right hemisphere stroke at the temporo-parietal junction of the infero-posterior parietal cortex. Neglect is characterized by reduced awareness of stimuli presented on patients’ contralesional side of space. Inspired by evidence of increased spatial exploration of patients’ left side achieved during keyboard scale-playing, the current study employed a music intervention that involved making sequential goal-directed actions in the neglected part of space, in order to determine whether this would bring about clinically significant improvement in chronic neglect. Two left neglect patients completed an intervention comprising four weekly 30-min music intervention sessions involving playing scales and familiar melodies on chime bars from right to left. Two cancellation tests [Mesulam shape, Behavioral Inattention Test (BIT) star], the neglect subtest from the computerized TAP (Test of Attentional Performance) battery, and the line bisection test were administered three times during a preliminary baseline phase, before and after the four intervention sessions during the intervention phase to investigate short-term effects, and 1 week after the last intervention session to investigate whether any changes in performance would persist. Both patients demonstrated significant short-term and longer-lasting improvements on the Mesulam shape cancellation test. One patient also showed longer-lasting effects on the BIT star cancellation test and scored in the normal range 1 week after the intervention. These findings provide preliminary evidence that active music-making with a horizontally aligned instrument may help neglect patients attend more to their affected side.
PMCID: PMC4052745  PMID: 24966827
neglect; stroke; rehabilitation; music therapy; motivation; auditory–motor; spatial attention
12.  Effect of Eye Patching in Rehabilitation of Hemispatial Neglect 
Eye patching (EP; monocular or right hemifield) has been proposed to improve visuospatial attention to the ignored field in patients with hemispatial neglect. The aim of this paper is to review the literature on the effects of EP in hemispatial neglect after stroke in order to convey evidence-based recommendations to clinicians in stroke rehabilitation. Thirteen intervention studies were selected from the Medline, EMBASE, Scopus, Cochrane Library, CINAHL, PsychINFO, EBRSR, and Health Star databases. Methodological quality was defined according to the Physiotherapy Evidence Database. Overall, seven studies used monocular EP, five used right hemifield patching, and one compared right monocular with right hemifield patching. Seven studies compared normal viewing to monocular or hemifield patching conditions. Six studies included a period of treatment. As to the monocular EP, four studies reported positive effects of right monocular patching. One study showed an improvement in hemispatial neglect with left monocular patching. Two studies found no superiority of right vs. left monocular patching. One study found no effects of right monocular patching. As to the right hemifield EP, one study showed improvements in neglect after right hemifield patching. Three studies found that right hemifield patching combined with another rehabilitation technique was more effective than that treatment alone. One study found no differences between right hemifield patching combined with another treatment and that treatment alone. One study found the same effect between right hemifield patching alone and another rehabilitation technique. Our results globally tend to support the usefulness of right hemifield EP in clinical practice. In order to define a level of evidence with the standard rehabilitation evidence rating tools, further properly powered randomized controlled trials or meta-analysis are needed.
PMCID: PMC3759299  PMID: 24032011
hemispatial neglect; rehabilitation; perceptual disorders; treatment; stroke; visual stimulation; superior colliculus; eye patching
13.  Rotigotine transdermal system and evaluation of pain in patients with Parkinson’s disease: a post hoc analysis of the RECOVER study 
BMC Neurology  2014;14:42.
Pain is a troublesome non-motor symptom of Parkinson’s disease (PD). The RECOVER (Randomized Evaluation of the 24-hour Coverage: Efficacy of Rotigotine; NCT00474058) study demonstrated significant improvements in early-morning motor function (UPDRS III) and sleep disturbances (PDSS-2) with rotigotine transdermal system. Improvements were also reported on a Likert pain scale (measuring any type of pain). This post hoc analysis of RECOVER further evaluates the effect of rotigotine on pain, and whether improvements in pain may be attributable to benefits in motor function or sleep disturbance.
PD patients with unsatisfactory early-morning motor impairment were randomized to optimal-dose (up to 16 mg/24 h) rotigotine or placebo, maintained for 4 weeks. Pain was assessed in the early-morning using an 11-point Likert pain scale (rated average severity of pain (of any type) over the preceding 12 hours from 0 [no pain] to 10 [worst pain ever experienced]). Post hoc analyses for patients reporting ‘any’ pain (pain score ≥1) at baseline, and subgroups reporting ‘mild’ (score 1–3), and ‘moderate-to-severe’ pain (score ≥4) were performed. Likert pain scale change from baseline in rotigotine-treated patients was further analyzed based on a UPDRS III/PDSS-2 responder analysis (a responder defined as showing a ≥30% reduction in early morning UPDRS III total score or PDSS-2 total score). As post hoc analyses, all p values presented are exploratory.
Of 267 patients with Likert pain data (178 rotigotine, 89 placebo), 187 (70%) reported ‘any’ pain; of these 87 (33%) reported ‘mild’, and 100 (37%) ‘moderate-to-severe’ pain. Change from baseline pain scores decreased with rotigotine compared with placebo in patients with ‘any’ pain (-0.88 [95% CI: -1.56, -0.19], p = 0.013), and in the subgroup with ‘moderate-to-severe’ pain (-1.38 [-2.44, -0.31], p = 0.012). UPDRS III or PDSS-2 responders showed greater improvement in pain than non-responders.
The results from this post hoc analysis of the RECOVER study suggest that pain was improved in patients with PD treated with rotigotine; this may be partly attributable to benefits in motor function and sleep disturbances. Prospective studies are warranted to investigate this potential benefit and the clinical relevance of these findings.
PMCID: PMC4016269  PMID: 24602411
Parkinson's disease; Pain; Rotigotine; Dopamine receptor agonist
14.  The Effect of Stimulus Duration and Motor Response in Hemispatial Neglect during a Visual Search Task 
PLoS ONE  2012;7(5):e37369.
Patients with hemispatial neglect exhibit a myriad of profound deficits. A hallmark of this syndrome is the patients' absence of awareness of items located in their contralesional space. Many studies, however, have demonstrated that neglect patients exhibit some level of processing of these neglected items. It has been suggested that unconscious processing of neglected information may manifest as a fast denial. This theory of fast denial proposes that neglected stimuli are detected in the same way as non-neglected stimuli, but without overt awareness. We evaluated the fast denial theory by conducting two separate visual search task experiments, each differing by the duration of stimulus presentation. Specifically, in Experiment 1 each stimulus remained in the participants' visual field until a response was made. In Experiment 2 each stimulus was presented for only a brief duration. We further evaluated the fast denial theory by comparing verbal to motor task responses in each experiment. Overall, our results from both experiments and tasks showed no evidence for the presence of implicit knowledge of neglected stimuli. Instead, patients with neglect responded the same when they neglected stimuli as when they correctly reported stimulus absence. These findings thus cast doubt on the concept of the fast denial theory and its consequent implications for non-conscious processing. Importantly, our study demonstrated that the only behavior affected was during conscious detection of ipsilesional stimuli. Specifically, patients were slower to detect stimuli in Experiment 1 compared to Experiment 2, suggesting a duration effect occurred during conscious processing of information. Additionally, reaction time and accuracy were similar when reporting verbally versus motorically. These results provide new insights into the perceptual deficits associated with neglect and further support other work that falsifies the fast denial account of non-conscious processing in hemispatial visual neglect.
PMCID: PMC3360686  PMID: 22662149
15.  Overnight switch from ropinirole to transdermal rotigotine patch in patients with Parkinson disease 
BMC Neurology  2011;11:100.
A recent trial involving predominantly Caucasian subjects with Parkinson Disease (PD) showed switching overnight from an oral dopaminergic agonist to the rotigotine patch was well tolerated without loss of efficacy. However, no such data have been generated for Korean patients.
This open-label multicenter trial investigated PD patients whose symptoms were not satisfactorily controlled by ropinirole, at a total daily dose of 3 mg to 12 mg, taken as monotherapy or as an adjunct to levodopa. Switching treatment from oral ropinirole to transdermal rotigotine was carried out overnight, with a dosage ratio of 1.5:1. After a 28-day treatment period, the safety and tolerability of switching was evaluated. Due to the exploratory nature of this trial, the effects of rotigotine on motor and nonmotor symptoms of PD were analyzed in a descriptive manner.
Of the 116 subjects who received at least one treatment, 99 (85%) completed the 28-day trial period. Dose adjustments were required for 11 subjects who completed the treatment period. A total of 76 treatment-emergent adverse events (AEs) occurred in 45 subjects. No subject experienced a serious AE. Thirteen subjects discontinued rotigotine prematurely due to AEs. Efficacy results suggested improvements in both motor and nonmotor symptoms and quality of life after switching. Fifty-two subjects (46%) agreed that they preferred using the patch over oral medications, while 31 (28%) disagreed.
Switching treatment overnight from oral ropinirole to transdermal rotigotine patch, using a dosage ratio of 1.5:1, was well tolerated in Korean patients with no loss of efficacy.
Trial registration
This trial is registered with the Registry (NCT00593606).
PMCID: PMC3166898  PMID: 21831297
16.  Transdermal rotigotine for the perioperative management of restless legs syndrome 
BMC Neurology  2012;12:106.
Immobilisation, blood loss, sleep deficiency, and (concomitant) medications during perioperative periods might lead to acute exacerbation of symptoms in patients with the restless legs syndrome (RLS). Continuous transdermal delivery of the dopamine agonist rotigotine provides stable plasma levels over 24 h and may provide RLS patients with a feasible treatment option for perioperative situations. To assess the feasibility of use of rotigotine transdermal patch for the perioperative management of moderate to severe RLS, long-term data of an open-label extension of a rotigotine dose-finding study were retrospectively reviewed.
The data of all 295 patients who had entered the 5-year study were screened independently by two reviewers for the occurrence of surgical interventions during the study period. The following data were included in this post-hoc analysis: patient age, sex, surgical intervention and outcome, duration of hospital stay, rotigotine maintenance dose at the time of surgery, rotigotine dose adjustment, and continuation/discontinuation of rotigotine treatment. All parameters were analysed descriptively. No pre-specified efficacy assessments (e.g. IRLS scores) were available for the perioperative period.
During the study period, 61 surgical interventions were reported for 52 patients (median age, 63 years; 67% female); the majority of patients (85%) had one surgical intervention. The mean rotigotine maintenance dose at time of surgery was 3.1 ± 1.1 mg/24 h. For most interventions (95%), rotigotine dosing regimens were maintained during the perioperative period. Administration was temporarily suspended in one patient and permanently discontinued in another two. The majority (96%) of the patients undergoing surgery remained in the study following the perioperative period and 30 of these patients (61%) completed the 5-year study.
Although the data were obtained from a study which was not designed to assess rotigotine use in the perioperative setting, this post-hoc analysis suggests that treatment with rotigotine transdermal patch can be maintained during the perioperative period in the majority of patients and may allow for uninterrupted alleviation of RLS symptoms.
Trial Registration
The 5-year rotigotine extension study is registered with, identifier NCT00498186.
PMCID: PMC3577642  PMID: 23009552
17.  Spatial analysis after perinatal stroke: patterns of neglect and exploration in extra-personal space 
Brain and Cognition  2012;79(2):107-116.
This study was conducted to determine whether school-aged children who had experienced a perinatal stroke demonstrate evidence of persistent spatial neglect, and if such neglect was specific to the visual domain or was more generalized. Two studies were carried out. In the first, 38 children with either left hemisphere (LH) or right hemisphere (RH) damage and 50 age-matched controls were given visual cancellation tasks varying in two factors: target stimuli and stimulus array. In the second study, tactile neglect was evaluated in 41 children with LH or RH damage and 72 age-matched controls using a blindfolded manual exploration task. On the visual cancellation task, LH subjects omitted more target stimuli on the right, but also on the left, compared with controls. Children with RH lesions also produced a larger number of omissions on both the left and right sides than controls, but with poorer performance on the left. On the manual exploration task, LH children required significantly longer times to locate the target on both sides of the board than did controls. RH children had significantly prolonged search times on the left side, but not on the right, compared with controls. In both tasks, LH subjects employed unsystematic search strategies more often than both control and RH children. The search strategy of RH children also tended to be erratic when compared to controls, but only in the random arrays of the visual cancellation tasks; structure of the target stimuli improved their organization. These results demonstrate that children with early LH brain damage display bilateral difficulties in visual and tactile modalities; a pattern that is in contrast to that seen in adults with LH damage. This may result from disorganized search strategies or other subtle spatial or attentional deficits. Results of performance of RH children suggests the presence of contralateral neglect in both the visual and tactile modalities; a finding that is similar to the neglect in adult stroke patients with RH lesions. The fact that deficits in spatial attention and organizational strategies are present after very early focal damage to either the LH or the RH broadens our understanding of the differences in functional lateralization between the immature and mature brain. These results also add to evidence for limitations to plasticity in the developing brain. Our findings may have therapeutic and rehabilitative implications for the management of children with early focal brain lesions.
PMCID: PMC3381944  PMID: 22475578
spatial neglect; perinatal stroke; extrapersonal space; tactile neglect; visual neglect
18.  Right hemisphere dysfunction is better predicted by emotional prosody impairments as compared to neglect 
Neurologists generally consider hemispatial neglect to be the primary cognitive deficit following right hemisphere lesions. However, the right hemisphere has a critical role in many cognitive, communication and social functions; for example, in processing emotional prosody (tone of voice). We tested the hypothesis that impaired recognition of emotional prosody is a more accurate indicator of right hemisphere dysfunction than is neglect.
We tested 28 right hemisphere stroke (RHS) patients and 24 hospitalized age and education matched controls with MRI, prosody testing and a hemispatial neglect battery. Emotion categorization tasks assessed recognition of emotions from prosodic cues. Receiver operating characteristic (ROC) analyses were used to compare tests in their ability to distinguish stroke patients from controls.
ROC analyses revealed that the Prosody Score was more effective than the Neglect Battery Score in distinguishing stroke patients from controls, as measured by area under the curve (AUC); Prosody Score = 0.84; Neglect Battery Score =0. 57. The Prosody Score correctly classified 78.9%, while Neglect Score correctly classified 55.8% of participants as patients versus controls. The Prosody Score was similar to the total NIH Stroke Scale in identifying RHS patients (AUC=0.86, correctly classifying 80.1% of patients versus controls), but the tests only partially overlapped in the patients identified.
Severe prosody impairment may be a better indicator of right hemisphere dysfunction than neglect. Larger studies are needed to determine if including a bedside test of Prosody with the NIH Stroke Scale would most efficiently and reliably identify right hemisphere ischemia.
PMCID: PMC4059678  PMID: 24945016
prosody; neglect; emotions; stroke; right hemisphere; communication
19.  Therapeutic Effects of Caloric Stimulation and Optokinetic Stimulation on Hemispatial Neglect 
Hemispatial neglect refers to a cognitive disorder in which patients with unilateral brain injury cannot recognize or respond to stimuli located in the contralesional hemispace. Hemispatial neglect in stroke patients is an important predictor for poor functional outcome. Therefore, there is a need for effective treatment for this condition. A number of interventions for hemispatial neglect have been proposed, although an approach resulting in persistent improvement is not available. Of these interventions, our review is focused on caloric stimulation and optokinetic stimulation. These lateralized or direction-specific stimulations of peripheral sensory systems can temporarily improve hemispatial neglect. According to recent functional MRI and PET studies, this improvement might result from the partial (re)activation of a distributed, multisensory vestibular network in the lesioned hemisphere, which is a part of a system that codes ego-centered space. However, much remain unknown regarding exact signal timing and directional selectivity of the network.
PMCID: PMC2854939  PMID: 20396481
Neglect; Caloric stimulation; Optokinetic stimulation; Vestibular cortex; Ego-centered space
20.  Prism adaptation does not alter object-based attention in healthy participants 
F1000Research  2013;2:232.
Hemispatial neglect (‘neglect’) is a disabling condition that can follow damage to the right side of the brain, in which patients show difficulty in responding to or orienting towards objects and events that occur on the left side of space. Symptoms of neglect can manifest in both space- and object-based frames of reference. Although patients can show a combination of these two forms of neglect, they are considered separable and have distinct neurological bases. In recent years considerable evidence has emerged to demonstrate that spatial symptoms of neglect can be reduced by an intervention called prism adaptation. Patients point towards objects viewed through prismatic lenses that shift the visual image to the right. Approximately five minutes of repeated pointing results in a leftward recalibration of pointing and improved performance on standard clinical tests for neglect. The understanding of prism adaptation has also been advanced through studies of healthy participants, in whom adaptation to leftward prismatic shifts results in temporary neglect-like performance. Here we examined the effect of prism adaptation on the performance of healthy participants who completed a computerised test of space- and object-based attention. Participants underwent adaptation to leftward- or rightward-shifting prisms, or performed neutral pointing according to a between-groups design. Significant pointing after-effects were found for both prism groups, indicating successful adaptation. In addition, the results of the computerised test revealed larger reaction-time costs associated with shifts of attention between two objects compared to shifts of attention within the same object, replicating previous work. However there were no differences in the performance of the three groups, indicating that prism adaptation did not influence space- or object-based attention for this task. When combined with existing literature, the results are consistent with the proposal that prism adaptation may only perturb cognitive functions for which normal baseline performance is already biased.
PMCID: PMC3962007  PMID: 24715960
21.  The effect of dopamine agonists on cognitive functions in non-demented early-mild Parkinson’s disease patients  
Functional Neurology  2013;28(1): 13 - 18 .
The effect of dopamine agonists (DAs) on cognition in Parkinson’s disease (PD) is not yet completely established. Previous papers reported a worsening effect on some cognitive functions with some DAs, but not with others, suggesting that DAs may differently affect cognition in PD patients according to their pharmacological characteristics.
We set out to test the effect of rotigotine and cabergoline on cognitive functions in a group of forty non-demented early-mild PD patients (H &Y <2). Subjects were randomly divided into two groups and evaluated in a randomized cross-over study using neuropsychological tests; at the same time, motor function was monitored under three different treatment conditions: DA (rotigotine or cabergoline), L-dopa, and off therapy. Rotigotine and cabergoline were chosen because while they share a mixed D1 and D2 receptor profile, the former is non-ergolinic and the latter ergolinic.
No significant differences were found in cognitive function between the basal condition and the DA treatments. On the basis of the present data, which we compare with previous findings regarding pramipexole IR and pergolide, we hypothesize that combined stimulation of both dopamine receptor families, as occurs with rotigotine, cabergoline, L-dopa and pergolide, may preserve cognitive functions more than pure D2 family stimulation.
PMCID: PMC3812723  PMID: 23731911
cabergoline ;  cognition ;  pharmacokinetic ;  rotigotine
22.  Right sided hemispatial neglect and bilateral cerebral lesions. 
This study compared the frequency with which unilateral and bilateral cerebral disease gives rise to right sided visual hemispatial inattention. A retrospective survey identified brain injured patients for whom target omissions on visual target cancellation tasks significantly exceeded control values. Subjects consisted of 40 right handed patients referred for clinical evaluation or research study of hemispatial inattention. Right sided visual hemispatial inattention occurred with greater frequency and severity in patients with bilateral lesions than in patients with unilateral left sided or right sided lesions. All eight patients with bilateral lesions manifested right sided hemispatial inattention and failed to detect more targets overall than patients in the other two groups. Of the 13 patients with left sided lesion, seven ignored more targets on the right and six ignored more targets on the left. All but one of the 19 patients with right sided lesions ignored more targets on the left. The association of severe right sided visual hemispatial inattention with bilateral cerebral disease extends previous findings and showed that, in this sample, the most common setting for right sided hemispatial neglect occurred in patients with bilateral cerebral lesions.
PMCID: PMC1073864  PMID: 8609518
23.  Visual Hemispatial Neglect, Re-Assessed 
Increased computer use in clinical settings offers an opportunity to develop new neuropsychological tests that exploit the control computers have over stimulus dimensions and timing. However, before adopting new tools, empirical validation is necessary. In the current study, our aims were twofold: to describe a computerized adaptive procedure with broad potential for neuropsychological investigations, and to demonstrate its implementation in testing for visual hemispatial neglect. Visual search results from adaptive psychophysical procedures are reported from 12 healthy individuals and 23 individuals with unilateral brain injury. Healthy individuals reveal spatially symmetric performance on adaptive search measures. In patients, psychophysical outcomes (as well as those from standard paper-and-pencil search tasks) reveal visual hemispatial neglect. Consistent with previous empirical studies of hemispatial neglect, lateralized impairments in adaptive conjunction search are greater than in adaptive feature search tasks. Furthermore, those with right hemisphere damage show greater lateralized deficits in conjunction search than do those with left hemisphere damage. We argue that adaptive tests, which automatically adjust to each individual’s performance level, are efficient methods for both clinical evaluations and neuropsychological investigations, and have the potential to detect subtle deficits even in chronic stages, when flagrant clinical signs have frequently resolved.
PMCID: PMC2573467  PMID: 18282322
Neuropsychology; Visual Search; Diagnosis; Attention; Vision Tests; Perceptual Disorders
24.  Impaired perceptual memory of locations across gaze-shifts in patients with unilateral spatial neglect 
Journal of cognitive neuroscience  2007;19(8):1388-1406.
Right-hemisphere lesions often lead to severe disorders in spatial awareness and behavior, such as left hemispatial neglect. Neglect involves not only pathological biases in attention and exploration, but also deficits in internal representations of space and spatial working memory. Here we designed a new paradigm to test whether one potential component may involve a failure to maintain an updated representation of visual locations across delays when a gaze-shift intervenes. Right-hemisphere patients with varying severity of left spatial neglect had to encode a single target location and retain it across an interval of 2 or 3 seconds, during which the target was transiently removed, before a subsequent probe appeared for a same/different location judgment. During the delay, gaze could have to shift to either side of the remembered location, or no gaze-shift was required. Patients showed a dramatic loss of memory for target location after shifting gaze to its right (towards their ‘intact’ ipsilesional side), but not after leftward gaze-shifts. Such impairment arose even when the target initially appeared in the right visual field, before being updated leftward due to right gaze; and even when gaze returned to screen center before the memory probe was presented. These findings indicate that location information may be permanently degraded when the target has to be remapped leftward in gaze-centric representations. Across patients, the location-memory deficit induced by rightward gaze-shifts correlated with left neglect severity on several clinical tests. This paradoxical memory deficit, with worse performance following gaze-shifts to the ‘intact’ side of space, may reflect losses in gaze-centric representations of space that normally remap a remembered location dynamically relative to current gaze. Right gaze-shifts may remap remembered locations leftward, into damaged representations; whereas left gaze-shifts will require remapping rightward, into intact representations. Our findings accord with physiological data on normal remapping mechanisms in the primate brain, but demonstrate for the first time their impact on perceptual spatial memory when damaged, while providing new insights into possible components that may contribute to the neglect syndrome.
PMCID: PMC2601183  PMID: 17651010
spatial neglect; spatial memory; remapping; gaze; awareness
25.  Attention maps in the brain 
Over 20 distinct cerebral cortical areas contain spatial map representations of the visual field. These retinotopic, or visuotopic, cortical areas occur not only in the occipital lobe but also in the parietal, temporal, and frontal lobes. The cognitive influences of visuospatial attention operate via these cortical maps and can support selection of multiple objects at the same time. In early visual cortical areas, spatial attention enhances responses of selected items and diminishes the responses to distracting items. In higher order cortex, the maps support a spatial indexing role, keeping track of the items to be attended. These maps also support visual short-term memory (VSTM) representations. In each hemisphere, all the known maps respond selectively to stimuli presented within the contralateral visual field. However, a hemispheric asymmetry emerges when the attentional or VSTM demands of a task become significant. In the parietal lobe, the right hemisphere visuotopic maps switch from coding only contralateral visual targets to coding memory and attention targets across the entire visual field. This emergent asymmetry has important implications for understanding hemispatial neglect syndrome, and supports a dynamic network form of the representational model of neglect.
PMCID: PMC4118461  PMID: 25089167

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