Andreas Rogalewski

Transcranial direct current stimulation disrupts tactile perception

The excitability of the cerebral cortex can be modulated by various transcranial stimulation techniques. Transcranial direct current stimulation (tDCS) offers the advantage of portable equipment and could, therefore, be used for ambulatory modulation of brain excitability. However, modulation of cortical excitability by tDCS has so far mostly been shown by indirect measures. Therefore, we examined whether tDCS has a direct behavioral/perceptional effect. We compared tactile discrimination of vibratory stimuli to the left ring finger prior to, during and after tDCS applied for 7 min at 1‐mA current intensity in 13 subjects. Stimulation was pseudorandomized into cathodal, anodal and sham conditions in a within‐subject design. The active electrode was placed over the corresponding somatosensory cortex at C4 according to the 10–20 EEG system and the reference electrode at the forehead above the contralateral orbita. Cathodal stimulation compared with sham induced a prolonged decrease of tactile discrimination, while anodal and sham stimulation did not. Thus, cortical processing can be modulated in a behaviorally/perceptually meaningful way by weak transcranial current stimulation applied through portable technology. This finding offers a new perspective for the treatment of conditions characterized by alterations of cortical excitability.

Meta-Analysis of the Efficacy of Granulocyte-Colony Stimulating Factor in Animal Models of Focal Cerebral Ischemia

Background and Purpose— Recent reports have described the efficacy of the hematopoietic growth factor granulocyte-colony stimulating factor (G-CSF) in animal stroke models. Early clinical multicenter trials evaluating the effect of G-CSF in acute stroke and pilot clinical trials for the subacute phase are ongoing. To guide further development, a meta-analysis was performed to assess the effects of G-CSF on infarct size and sensorimotor deficits. Methods— Using electronic and manual searches of the literature, we identified studies describing the efficacy of G-CSF in animal models of focal cerebral ischemia. Two reviewers independently selected studies and extracted data on study quality, G-CSF doses, time of administration, and outcome measured as infarct volume and/or sensorimotor deficit. Data from all studies were pooled by meta-regression analyses. Results— Thirteen studies including 277 animals for infarct size calculation and 258 animals for assessment of sensorimotor deficit met the criteria for inclusion. Overall efficacy of G-CSF regarding infarct size reduction was 42%. Meta-regression analysis revealed a 0.8% (P<0.0001) decrease in infarct size per 1-&mgr;g/kg increase in G-CSF dose when applied within the first 6 hours and a 2.1% (P<0.0001) decrease when applied later than 6 hours after induction of ischemia with a significant (P=0.0004) greater infarct size reduction after delayed treatment. Sensorimotor deficits categorized into 3 subgroups improved between 24% and 40%. Conclusions— Our findings consolidate G-CSF as a drug that both reduces infarct size and enhances functional recovery. These effects are presumably dose dependent. In contrast to most other neuroprotectants, a beneficial outcome may also be achieved when treatment is delayed.

Toward a Multimodal Neuroprotective Treatment of Stroke

Background and Purpose— Stroke remains a common medical problem with importance attributable to the demographic changes in industrialized societies. Summary of Review— After years of setbacks, acute stroke therapy has finally emerged, including thrombolysis with tissue plasminogen activator (t-PA). However, t-PA treatment is limited by a narrow time window and side effects, so that only 3% of all stroke patients receive thrombolysis. Unimodal targeting of key events in stroke pathophysiology was not effective in providing long-term benefits, leading to negative results in previous clinical neuroprotective stroke trials. A successful future stroke therapy should approach multiple pathophysiological mechanisms besides revascularization at once, including reduction of t-PA–related side effects, prevention of cell death, stimulation of neuroregeneration, and plasticity. Conclusions— Strategies targeting these processes include multiple combination therapies as well as treatment with multimodal drugs that interact with these mechanisms. Here, we review such combination approaches, and outline how this concept could be developed into future stroke treatment.

The Efficacy of Erythropoietin and Its Analogues in Animal Stroke Models. A Meta-Analysis

Background and Purpose— Erythropoietin (EPO) was explored regarding its suitability as a candidate stroke drug in animal experimental studies. We performed a meta-analysis to obtain an overall impression of the efficacy of EPO in published animal experimental stroke studies and for potential guidance of future clinical studies. Methods— By electronic and manual searches of the literature, we identified studies describing the efficacy of EPO in experimental focal cerebral ischemia. Data on study quality, EPO dose, time of administration, and outcome measured as infarct volume or functional deficit were extracted. Data from all studies were pooled by means of a meta-analysis. Results— Sixteen studies were included in the meta-analysis. When administered after the onset of ischemia, EPO and its analogues reduced infarct size by 32% and improved neurobehavioral deficits significantly. A meta-regression suggests higher doses of EPO to be associated with smaller infarct volumes. When administered earlier than 6 hours EPO was more effective compared to a later treatment initiation. Both hematopoietic and nonhematopoietic EPO analogues showed efficacy in experimental stroke. Conclusion— In conclusion, this analysis further strengthens confidence in the efficacy of EPO and its analogues in stroke therapy. Nonhematopoietic EPO analogues which are known to have less systemic adverse effects compared to EPO are also promising candidate stroke drugs. Further experimental studies are required that evaluate the safety of a combination of EPO with thrombolysis and whether EPO is also effective in animals with comorbidity.

Effects of Granulocyte-Colony Stimulating Factor After Stroke in Aged Rats

Background and Purpose— In aged humans, stroke is a major cause of disability for which no neuroprotective measures are available. Granulocyte-colony stimulating factor (G-CSF), a member of the cytokine family of growth factors, promotes brain neurogenesis and improves functional outcome after stroke in young animals. We tested the hypothesis that G-CSF provides a restorative therapeutic benefit in aged animals. Methods— Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 19- to 20-month-old male Sprague-Dawley rats. One hour after reperfusion, the aged rats were treated daily with 15 &mgr;g/kg G-CSF and for 15 days total. Rats were behaviorally tested and the brains removed for analysis at 28 days poststroke. Results— G-CSF treatment after stroke exerted a robust and sustained beneficial effect on survival rate and running function. Transient improvement after G-CSF treatment could be observed for coordinative motor function on the inclined plane test and for working memory in the radial-arm maze test. At the cellular level, G-CSF treatment increased the number of proliferating cells in the subventricular zone and dentate gyrus and also increased the number of newborn neurons in the subventricular zone ipsilateral to the lesion. Conclusions— These results suggest that G-CSF treatment in aged rats has a survival-enhancing capacity and a beneficial effect on functional outcome, most likely through supportive cellular processes such as neurogenesis.

Stroke Knowledge Among Stroke Support Group Members

BACKGROUND AND PURPOSE Community stroke education is needed to improve early stroke recognition and reduce delays in the referral of stroke patients. In some regions, stroke support groups are important promoters of regional stroke education. However, there are no data about the level of stroke knowledge among support group members that support this promotional role. METHODS We performed a cross-sectional questionnaire survey among 11 German stroke support groups. The questionnaire asked for stroke knowledge and sociodemographic and medical data. Stroke knowledge was excellent if a participant knew (1) at least 2 stroke symptoms (good symptom knowledge) and (2) at least 2 stroke risk factors (good risk factor knowledge), as well as knowing (3) that immediate hospital admission or an emergency call is necessary in case of stroke (good action knowledge). RESULTS A total of 133 members (96.2%) of 11 stroke support groups took part in the study. Mean age was 65.3 years (SD 11.2 years). Fifty-four percent of subjects were female, 72.8% were retired, and 69.8% were stroke patients. Of the participants, 80.3% had good symptom knowledge, 64.7% had good risk factor knowledge, and 79.7% had good action knowledge. Stroke knowledge was excellent in 44.0% of subjects. Logistic regression analysis showed that age <70 years and not having had a stroke were significant predictors for excellent stroke knowledge. CONCLUSIONS Overall, members of stroke support groups are well informed about all aspects of modern stroke care. Because of their knowledge and personal experience, support groups should be viewed as important partners in community stroke education.

VZV brainstem encephalitis triggers NMDA receptor immunoreaction

After its discovery, anti-NMDA receptor (NMDAR) encephalitis was quickly recognized as “sleeping” neurologic disease, presumably heavily underestimated. This autoimmune disease is defined by the presence of immunoglobulin G (IgG) antibodies against cell surface epitopes of the NR1 subunit of the NMDAR.1 The disease phenotype is best characterized as encephalopathy and was initially described by Dalmau et al.2 in young women presenting with a prominent change of behavior, psychosis, memory deficits, seizures, abnormal movements, coma, and autonomic dysfunction. Whereas in cases of an underlying tumor (usually teratoma in the ovary) the cause of the disease is viewed as paraneoplastic, in many cases without a tumor the trigger for the NMDAR antibody production is unknown. Recently it has been observed that herpes simplex virus 1 (HSV-1) may account for relapses of HSV encephalitis (HSVE) by inducing NMDAR immunoreactivity causing the full clinical picture of anti-NMDA-R encephalopathy3 or a choreatic condition.4–6

Detection of atrial fibrillation in patients with embolic stroke of undetermined source by prolonged monitoring with implantable loop recorders

Recently, the clinical entity embolic stroke of undetermined source (ESUS) has been defined for patients with ischemic strokes, where neither a cardioembolic nor a non-cardiac source can be detected. These patients may suffer from asymptomatic atrial fibrillation (AF), terminating spontaneously and thus eluding detection. Implantable loop recorders (ILR) with automatic AF detection algorithms can detect short-lasting, subclinical AF. The aim of this study was to prospectively assess and predict AF detection in patients with ESUS using ILR with daily remote interrogation. Patients with acute ESUS received an ILR, were seen every 6 months and additionally interrogated their ILR daily using remote monitoring. The incidence of AF detection was assessed and parameters which might predict AF detection (clinical and from magnetic resonance tomography) were analysed. ILR implantation was performed in 123 patients on average 20 days after stroke. During a mean follow-up of 12.7±5.5 months, AF was documented and manually confirmed in 29 of 123 patients (23.6 %). First AF detection occurred on average after 3.6±3.4 months of monitoring. Patients with AF were on average older, had a higher CHA2DS2-VASc score and more often cerebral microangiopathy. In conclusion, AF can be documented in approximately 25 % of patients with the diagnosis of ESUS after careful work-up within a year of monitoring by an ILR and daily remote interrogation. This had important therapeutic consequences (initiation of anticoagulation for secondary stroke prevention) in these patients.

Forced arm use is superior to voluntary training for motor recovery and brain plasticity after cortical ischemia in rats.

Background and purposeBoth the immobilization of the unaffected arm combined with physical therapy (forced arm use, FAU) and voluntary exercise (VE) as model for enriched environment are promising approaches to enhance recovery after stroke. The genomic mechanisms involved in long-term plasticity changes after different means of rehabilitative training post-stroke are largely unexplored. The present investigation explored the effects of these physical therapies on behavioral recovery and molecular markers of regeneration after experimental ischemia.Methods42 Wistar rats were randomly treated with either forced arm use (FAU, 1-sleeve plaster cast onto unaffected limb at 8/10 days), voluntary exercise (VE, connection of a freely accessible running wheel to cage), or controls with no access to a running wheel for 10 days starting at 48 hours after photothrombotic stroke of the sensorimotor cortex. Functional outcome was measured using sensorimotor test before ischemia, after ischemia, after the training period of 10 days, at 3 and 4 weeks after ischemia. Global gene expression changes were assessed from the ipsi- and contralateral cortex and the hippocampus.ResultsFAU-treated animals demonstrated significantly improved functional recovery compared to the VE-treated group. Both were superior to cage control. A large number of genes are altered by both training paradigms in the ipsi- and contralateral cortex and the hippocampus. Overall, the extent of changes observed correlated well with the functional recovery obtained. One category of genes overrepresented in the gene set is linked to neuronal plasticity processes, containing marker genes such as the NMDA 2a receptor, PKC ζ, NTRK2, or MAP 1b.ConclusionsWe show that physical training after photothrombotic stroke significantly and permanently improves functional recovery after stroke, and that forced arm training is clearly superior to voluntary running training. The behavioral outcomes seen correlate with patterns and extent of gene expression changes in all brain areas examined. We propose that physical training induces a fundamental change in plasticity-relevant gene expression in several brain regions that enables recovery processes. These results contribute to the debate on optimal rehabilitation strategies, and provide a valuable source of molecular entry points for future pharmacological enhancement of recovery.

Semaphorin 6A Improves Functional Recovery in Conjunction with Motor Training after Cerebral Ischemia

Background We have previously identified Semaphorin 6a (Sema6A) as an upregulated gene product in a gene expression screen in cortical ischemia [1]. Semaphorin 6a was regulated during the recovery phase following ischemia in the cortex. Semaphorin 6a is a member of the superfamily of semaphorins involved in axon guidance and other functions. We hypothesized that the upregulation indicates a crucial role of this molecule in post-stroke rewiring of the brain. Here we have tested this hypothesis by overexpressing semaphorin 6a in the cortex by microinjection of a modified AAV2-virus. A circumscribed cortical infarct was induced, and the recovery of rats monitored for up to 4 weeks using a well-established test battery (accelerated rotarod training paradigm, cylinder test, adhesive tape removal). We observed a significant improvement in post-ischemic recovery of animals injected with the semaphorin 6a virus versus animals treated with a control virus. We conclude that semaphorin 6a overexpressed in the cortex enhances recovery after cerebral ischemia. Semaphorin 6a may represent a novel therapeutic candidate for the treatment of chronic stroke.