Correction to: Safety and efficacy of Cerebrolysin in acute brain injury and neurorecovery: CAPTAIN I-a randomized, placebo-controlled, double-blind, Asian-Pacific trial.

The above article was published online with incorrect abbreviations in Figures 2 and 3 last sentence of the legend. HDA should be corrected to HADS.

Safety and efficacy of Cerebrolysin in acute brain injury and neurorecovery: CAPTAIN I-a randomized, placebo-controlled, double-blind, Asian-Pacific trial.

OBJECTIVE: To evaluate the safety and efficacy of Cerebrolysin as an add-on therapy to local standard treatment protocol in patients after moderate-to-severe traumatic brain injury. METHODS: The patients received the study medication in addition to standard care (50 mL of Cerebrolysin or physiological saline solution daily for 10 days, followed by two additional treatment cycles with 10 mL daily for 10 days) in a prospective, randomized, double-blind, placebo-controlled, parallel-group, multi-centre phase IIIb/IV trial. The primary endpoint was a multidimensional ensemble of 14 outcome scales pooled to be analyzed by means of the multivariate, correlation-sensitive Wei-Lachin procedure. RESULTS: In 46 enrolled TBI patients (Cerebrolysin 22, placebo 24), three single outcomes showed stand-alone statistically significant superiority of Cerebrolysin [Stroop Word/Dots Interference (p = 0.0415, Mann-Whitney(MW) = 0.6816, 95% CI 0.51-0.86); Color Trails Tests 1 and 2 (p = 0.0223/0.0170, MW = 0.72/0.73, 95% CI 0.53-0.90/0.54-0.91), both effect sizes lying above the benchmark for "large" superiority (MW > 0.71)]. While for the primary multivariate ensemble, statistical significance was just missed in the intention-to-treat population (pWei-Lachin < 0.1, MWcombined = 0.63, 95% CI 0.48-0.77, derived standardized mean difference (SMD) 0.45, 95% CI -0.07 to 1.04, derived OR 2.1, 95% CI 0.89-5.95), the per-protocol analysis showed a statistical significant superiority of Cerebrolysin (pWei-Lachin = 0.0240, MWcombined = 0.69, 95% CI 0.53 to 0.85, derived SMD 0.69, 95% CI 0.09 to 1.47, derived OR 3.2, 95% CI 1.16 to 12.8), with effect sizes of six single outcomes lying above the benchmark for "large" superiority. Safety aspects were comparable to placebo. CONCLUSION: Our trial suggests beneficial effects of Cerebrolysin on outcome after TBI. Results should be confirmed by a larger RCT with a comparable multidimensional approach.

[Neurological rehabilitation]. / Neurologische Rehabilitation.

This article describes state of the art concepts of neurological rehabilitation in Germany. In parallel to enormous growth of knowledge in the neurosciences also neurological rehabilitation has made significant progress. The increasing use of concepts of evidence based medicine and an early translation of knowledge from the neurosciences into clinical rehabilitation practice contribute to therapeutic advances. It is now widely accepted, that rehabilitation should start early and should be organized in a multidisciplinary professional team. Therapeutic procedures selected should be evidence based and have to be modified to find custom tailored solutions for individual patients. General rules derived from neuroscientific knowledge have been shown to be useful to design new therapeutic techniques. Neuromodulatory stimulation and special pharmacological treatments provide further options for enhancing results of rehabilitation.

The German trial on Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE): a multicenter, randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Comprehensive treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major clinical challenge. The current therapy gold standard is aciclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains around 20% and a majority of survivors suffer from severe disability. Experimental research and recent retrospective clinical observations suggest a favourable therapy response to adjuvant dexamethasone. Currently there is no randomized clinical trial evidence, however, to support the routine use of adjuvant corticosteroid treatment in HSVE. METHODS: The German trial of Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE) studied the effect of adjuvant dexamethasone versus placebo on top of standard aciclovir treatment in adult patients aged 18 up to 85 years with proven HSVE in German academic centers of Neurology in a randomized and double blind fashion. The trial was open from November 2007 to December 2012. The initially planned sample size was 372 patients with the option to increase to up to 450 patients after the second interim analysis. The primary endpoint was a binary functional outcome after 6 months assessed using the modified Rankin scale (mRS 0-2 vs. 3-6). Secondary endpoints included mortality after 6 and 12 months, functional outcome after 6 months measured with the Glasgow outcome scale (GOS), functional outcome after 12 months measured with mRS and GOS, quality of life as measured with the EuroQol 5D instrument after 6 and 12 months, neuropsychological testing after 6 months, cranial magnetic resonance imaging findings after 6 months, seizures up to day of discharge or at the latest at day 30, and after 6 and 12 months. RESULTS: The trial was stopped prematurely for slow recruitment after 41 patients had been randomized, 21 of them treated with dexamethasone and 20 with placebo. No difference was observed in the primary endpoint. In the full analysis set (n = 19 in each group), 12 patients in each treatment arm achieved a mRS of 0-2. Similarly, we did not observe significant differences in the secondary endpoints (GOS, mRS, quality of life, neuropsychological testing). CONCLUSION: GACHE being prematurely terminated demonstrated challenges encountered performing randomized, placebo-controlled trials in rare life threatening neurological diseases. Based upon our trial results the use of adjuvant steroids in addition to antiviral treatment remains experimental and is at the decision of the individual treating physician. Unfortunately, the small number of study participants does not allow firm conclusions. TRIAL REGISTRATION: EudraCT-Nr. 2005-003201-81.

TENS and optokinetic stimulation in neglect therapy after cerebrovascular accident: a randomized controlled study.

BACKGROUND: In a randomized controlled type Ib study, the effectiveness of three different forms of therapy for the treatment of visual neglect was assessed by comparing therapy outcomes in three groups of patients after cerebrovascular accidents. METHODS: A control group received only standard exploration training, whilst the second and third group received exploration training combined with either contralateral transcutaneous electrical nerve stimulation (TENS) or optokinetic stimulation (OKS) respectively. RESULTS: It was found that exploration training alone resulted in no improvement on both standard neglect tests (NTs) and everyday-relevant measures of reading and writing performance. In contrast, the groups receiving TENS or OKS showed significant improvements in both sets of measures with the difference that for the TENS group the improvement in NT scores at the end of therapy had disappeared 1-week later. However, both treatments resulted in significant improvements in reading and writing which were still present upon retesting 1-week after the end of therapy. CONCLUSION: Both methods can be recommended for neglect therapy and are superior to exploration therapy alone.

Differential effect of Huntington's and Parkinson's diseases in programming motor sequences of varied lengths.

BACKGROUND: Parkinson's disease (PD) and Huntington's disease (HD) patients have difficulties executing sequential movements. Attention control and short-term memory probably play an important role in programming sequential movements. To investigate the contribution of these cognitive factors to programming and executing visuomotor sequences in HD and PD patients a computerized version of the Corsi Block Tapping-Test was employed. METHODS: the performance of 11 patients with early stage PD, 11 HD patients with borderline to mild caudate atrophy and 20 healthy subjects was compared. The task was a reaction time task where targets were illuminated in groups of sequences increasing from 2 items to 5 items. Subjects reproduced the sequence (pressing the illuminated target) in the same order of appearance. Reaction Times and movement times were recorded. RESULTS: PD patients had increasing difficulties in programming and executing series greater than three components. HD patients did not differ significantly from the controls, although they showed a tendency to lose accuracy in the longer series. Both patient groups did not differ in their attention span. CONCLUSIONS: In PD although the spatial information may be well stored, they have difficulty accessing it when their attention is overloaded, leading to poor encoding and slow information processing. This process interferes with programming and execution of movement sequences. HD patients in the early stages of the illness seem to have more attention resources than PD patients, so that they start to show more problems in executing visuomotor sequences with longer movement sequences than PD patients.

Benign symmetric lipomatosis with axonal neuropathy and abnormalities in specific mitochondrial tRNA regions.

Benign symmetric lipomatosis, also called Madelung's disease, is characterized by lipomata and fatty infiltrations. Involvement of the nervous system has occasionally been described, mitochondrial dysfunctions have been suggested. We report a 55 year old male suffering from benign symmetric lipomatosis with associated axonal neuropathy and hyperlipoproteinemia. He showed a remarkable phenotype of neuropathy i.e. no sensory disturbance, ubiquitous fasciculations and muscle cramps, furthermore reduced COX activity and abnormalities in specific mitochondrial tRNA regions.

Cingulate cortex activation and competing responses: the role of preparedness for competition.

Regional cerebral blood flow (rCBF) was studied in a task, where a preparatory stimulus (S1) cued for an imperative second stimulus (S2) which was associated with a response. Two preparatory stimuli cued unequivocally each for one response. In contrast, a third preparatory stimulus cued for two response alternatives which appeared for the same ratio (each in 50% of all trials) introducing response competition. In a first experimental condition, non-arbitrary, unambiguous stimuli were used as S1 to enable the subjects to prepare their responses. In a second and third scan, arbitrary preparatory stimuli were used during different stages of awareness for the S1-S2 association. Subjects performed this task "naive" without knowledge about the S1-S2 association and also in an experimental condition being aware of the S1-S2 association. Button presses after unambiguous, non-arbitrary preparatory stimuli activated the right middle frontal gyrus and inferior parietal lobe if S1 was associated with a definite response. When the subjects did not know the S1-S2 relation, left prefrontal cortex activation was associated with trials including definite responses. Performing the same S1-S2 response condition after subjects knew their relation right prefrontal and left parietal areas became additionally engaged. However, in the first experimental condition using unambiguous, non-arbitrary stimuli and in the third, "aware" experimental condition when S1 was coupled with two response alternatives, the anterior cingulate cortex was activated. As these experimental conditions have in common, that the preparatory stimulus shares information about the upcoming competing response alternatives they highlight the evaluative role of the anterior cingulate cortex for competing actions.

Control of posture in patients with neurologically asymptomatic HIV infection and patients with beginning HIV-1-related encephalopathy.

OBJECTIVE: Stance control measurements (sway velocity, sway area, and postural reflexes) were performed in 36 patients with neurologically asymptomatic human immunodeficiency virus infection (HIV) and in 10 patients with beginning HIV type 1 (HIV-1)-related encephalopathy. All recordings were performed using a movable platform system. OBSERVATIONS: Static posturography and postural reflexes revealed pathologic results in patients with beginning HIV-1-related encephalopathy and in about 25% of patients with nonsymptomatic HIV infection in comparison with age- and sex-matched control subjects. CONCLUSIONS: Postural control is well preserved in early HIV infection; thus, it is not an appropriate measure for detecting subclinical deficits, but disturbances of postural control seem to be one of the first neurological abnormalities in patients with beginning HIV-1-related encephalopathy.

Visual hallucinations in recovery from cortical blindness: imaging correlates.

OBJECTIVE: To investigate the cerebral metabolic and functional patterns during recovery from cortical blindness. DESIGN: Follow-up study with serial clinical, metabolic, and functional imaging and visual evoked potentials. CASE PRESENTATION: A 24-year-old woman suffered from cortical blindness after cardiac arrest and recovered over a 6-month period. During recovery, she experienced complex visual hallucinations that could be initiated by visual imagery. RESULTS: Initially, the regional cerebral metabolic rate of glucose was severely reduced in the visual and parieto-occipital cortex bilaterally but recovered almost completely. Visual hallucinations led to significant increases of the regional cerebral blood flow in the initially severely hypometabolic parieto-occipital and temporo-lateral cortex. CONCLUSIONS: Recovery of vision was related to normalization of the postlesionally dysfunctional cortex. Visual hallucinations appeared as the clinical correlate of the electrophysiological hyperexcitability of the recovering partially damaged visual cortex.

Motor training in the therapy of Parkinson's disease.

Motor training techniques may be a helpful adjunct to medical treatment in improving motor function in patients with Parkinson's disease. Rational physical therapy should be based on a detailed understanding of the underlying nature of the motor deficit in Parkinson's disease. The design of training techniques should take into account the known neurophysiologic aspects of motor impairment in Parkinson's disease, such as the inability to initiate movement (akinesia), the inability to perform sequential movements, impairments in the pacing of rhythmic movements, and impairments in the predictability of movements. Training techniques are definitely necessary to prevent the sequelae, especially of the later stages of the disease, including contractures and muscle spasm. To increase voluntary motor activity, physiotherapeutic approaches must take into account specific aspects of the motor control deficit in Parkinson's disease. For example, physical therapy should emphasize large-amplitude movements and truncal activities and make use of cuing as a major facilitator in achieving rhythmic movement patterns. In addition, the psychosocial integration of the patient may be improved by physical exercises, particularly if these are provided in group therapy sessions.

Sound localization in egocentric space following hemispheric lesions.

In this paper the performance of patients with unilateral hemispheric lesions (n = 10 with right brain damage; n = 10 with left brain damage) on a free-field sound localization task was contrasted with that of healthy controls (n = 10). Sound stimuli were presented binaurally in the horizontal plane from eight loudspeakers set at azimuths between -105 degrees and +105 degrees. Whereas performance of both patient groups was generally less accurate than controls, no evidence suggested that this was specific to the contralateral hemisphere. The results indicate that both hemispheres play a role in sound localization, with systematic directional errors made towards the ipsilateral hemifield following unilateral lesions. Furthermore, particular location difficulties at pericentral positions (+15 degrees and -15 degrees) following right hemisphere damage, may indicate a specific function for the right hemisphere in determining personal frames of spatial reference within pericentral space.

Auditory sustained attention is a marker of unilateral spatial neglect.

The relationships between performance on a non-spatially-lateralized measure of sustained attention and spatial bias on tests sensitive to unilateral neglect were considered in a group of 44 patients with right hemisphere lesions following stroke. As predicted from earlier studies showing a strong association between unilateral spatial neglect and sustained attention, performance on a brief and monotonous tone-counting measure formed a significant predictor of spatial bias across a variety of measures of unilateral visual neglect. This study provides further evidence for a very close link between two attentional systems hitherto regarded as being quite separate, namely a spatial attention system implicated in unilateral neglect and a sustained attention system. A close connection between these two systems was predicted by Posner, who argued that the right hemisphere-dominant sustained attention system provides a strong modulatory influence on the functioning of the lateralized posterior attention system.

Cerebral visual motion blindness: transitory akinetopsia induced by transcranial magnetic stimulation of human area V5.

The perception of visual motion can be selectively and reversibly compromised by transcranial magnetic stimulation (TMS) of a small region of cortex, roughly 1 cm in diameter and corresponding in position to human area V5. The reversible inactivation of a small and specialized visual area which receives its predominant input from area V1 and sends a powerful return (re-entrant) input back to it allowed us to study for the first time the backward influence of area V5 on area V1. In contrast to the complete and temporary visual motion blindness which occurs during stimulation of V5, a less-prominent interference with the perception of visual motion occurs at 70-80 ms after the onset of the visual stimulus when TMS is applied to V1. Because V5 is critical for the perception of coherent motion, and because an intact re-entry of signals from V5 to V1 is essential for the conscious perception of visual motion, the results obtained with stimulation of V1 must be caused by a disruption of the re-entrant signals from V5 to V1.

Conditional associative learning is impaired in cerebellar disease in humans.

Eight patients with lesions restricted to the cerebellum were compared with a total of 25 age-matched controls on a reaction time (RT) task allowing the recording of simple and choice RTs as well as RTs to abstract visual patterns signifying the particular movement to be performed. In all conditions the actual movements required (either a left or a right button press) remained the same, but the cognitive requirements of the task varied. In the abstract patterns condition, the significance of the various patterns with regard to the required movement had to be learned by the subjects. The patients with cerebellar lesions were particularly impaired in this condition. It is concluded that the cerebellum is involved not just in the timing of movements but also in the decision process as to which movement should be performed under particular circumstances.

Successive roles of the cerebellum and premotor cortices in trajectorial learning.

The structures of the human brain engaged during learning of unilateral trajectorial hand movements were mapped by measurements of regional cerebral blood flow. Trajectorial movement velocity accelerated moderately after short-term training p < 0.025 and increased further after long-term training p < 0.01. During the early phase of learning there was a significant activation p < 0.001 of the ipsilateral dentate nucleus. By contrast, after overlearning the premotor cortical areas in both cerebral hemispheres were maximally activated p < 0.001, while the dentate nucleus was no longer activated. It is suggested that learning of new movement trajectories involves the cerebellum, while overlearned trajectorial movements engage the premotor cortex.

Motor learning by imagery is differentially affected in Parkinson's and Huntington's diseases.

Studies of motor imagery and motor learning have thus far been concerned only with its effects on healthy subjects. Therefore, in order to investigate the possible involvement of the basal ganglia, the effectiveness of motor imagery in the acquisition of motor constants in a graphomotor trajectorial learning task was examined in 11 non-demented mildly affected Huntington's disease (HD) patients and 12 non-demented Parkinson's disease (PD) patients. The patients received, after baseline, 10 min of motor imagery training, followed by a motor practice phase. Additionally, a test battery for visual imagery abilities was administered in order to investigate possible relations between visual and motor imagery. The results showed that imagery training alone enabled the HD patients to achieve a significant approach to movement isochrony, whereas the PD patients showed no marked improvements, either with motor imagery or with motor practice. Furthermore, the PD patients had more difficulties than the HD patients in solving the visual imagery tasks. Subsequent correlational analysis revealed significant relationships between the degree of caudate atrophy in the HD patients and their performance in the visual imagery tasks. However, there were no substantial correlations between the performance on the visual imagery tasks and the improvement of motor performance through motor imagery, which indicates that visual and motor imagery are independent processes. It is suggested that the dopaminergic input to the basal ganglia plays an important role in the translation of motor representations into motor performance, whereas the caudate nucleus atrophy of the HD patients does not seem to affect motor imagery, but only the visual imagery process. Furthermore, the deficits found in PD patients might also be related to their limited attentional resources and difficulties in employing predictive motor strategies.

A mental route to motor learning: improving trajectorial kinematics through imagery training.

There are contrasting reports upon the level of effectiveness of motor imagery in learning new motor skills, but there is general consensus that motor imagery can lead to improvements in performance, especially in combination with physical practice. In the present study we examined the effectiveness of motor imagery in the acquisition of movement invariants in two grapho-motor trajectorial learning tasks with differing visuospatial components: 'Ideogram drawing' and 'connecting circles'. Two subject groups were studied: An imagery group, which underwent 10 min of motor imagery training and a control group, which practised a control visuomotor task over the same period of time. The results showed that imagery training alone enabled the subjects to achieve a significant approach to movement isochrony as well as a significant shifting of peak velocity toward the target. After a practice phase, both groups improved their performance, but the imagery group was still significantly faster than the control group. Furthermore, a series of tests measuring visual imagery abilities was administered to the subjects. There were however no significant relationships between the motor performance and the visual imagery ability levels of the subjects. It is concluded that motor imagery can improve the acquisition of the spatio-temporal patterns of grapho-motor trajectories and that there are different processes involved in visual and motor imagery.