On the importance of long-term functional assessment after stroke to improve translation from bench to bedside

Despite extensive research efforts in the field of cerebral ischemia, numerous disappointments came from the translational step. Even if experimental studies showed a large number of promising drugs, most of them failed to be efficient in clinical trials. Based on these reports, factors that play a significant role in causing outcome differences between animal experiments and clinical trials have been identified; and latest works in the field have tried to discard them in order to improve the scope of the results. Nevertheless, efforts must be maintained, especially for long-term functional evaluations. As observed in clinical practice, animals display a large degree of spontaneous recovery after stroke. The neurological impairment, assessed by basic items, typically disappears during the firsts week following stroke in rodents. On the contrary, more demanding sensorimotor and cognitive tasks underline other deficits, which are usually long-lasting. Unfortunately, studies addressing such behavioral impairments are less abundant. Because the characterization of long-term functional recovery is critical for evaluating the efficacy of potential therapeutic agents in experimental strokes, behavioral tests that proved sensitive enough to detect long-term deficits are reported here. And since the ultimate goal of any stroke therapy is the restoration of normal function, an objective appraisal of the behavioral deficits should be done

Sodium-Dependent Vitamin C Transporter 2 (SVCT2) Expression and Activity in Brain Capillary Endothelial Cells after Transient Ischemia in Mice

Expression and transport activity of Sodium-dependent Vitamin C Transporter 2 (SVCT2) was shown in various tissues and organs. Vitamin C was shown to be cerebroprotective in several animal models of stroke. Data on expression, localization and transport activity of SVCT2 after cerebral ischemia, however, has been scarce so far. Thus, we studied the expression of SVCT2 after middle cerebral artery occlusion (MCAO) in mice by immunohistochemistry. We found an upregulation of SVCT2 after stroke. Co-stainings with Occludin, Von-Willebrand Factor and CD34 demonstrated localization of SVCT2 in brain capillary endothelial cells in the ischemic area after stroke. Time-course analyses of SVCT2 expression by immunohistochemistry and western blots showed upregulation in the subacute phase of 2–5 days. Radioactive uptake assays using 14C-labelled ascorbic acid showed a significant increase of ascorbic acid uptake into the brain after stroke. Taken together, these results provide evidence for the expression and transport activity of SVCT2 in brain capillary endothelial cells after transient ischemia in mice. These results may lead to the development of novel neuroprotective strategies in stroke therapy

Attenuation of N2 amplitude of laser-evoked potentials by theta burst stimulation of primary somatosensory cortex

Theta burst stimulation (TBS) is a special repetitive transcranial magnetic stimulation (rTMS) paradigm, where bursts of low-intensity stimuli are applied in the theta frequency. The aim of this study was to investigate the effect of neuronavigated TBS over primary somatosensory cortex (SI) on laser-evoked potentials (LEPs) and acute pain perception induced with Tm : YAG laser stimulation. The amplitude changes of the N1, N2, and P2 components of LEPs and related subjective pain rating scores of 12 healthy subjects were analyzed prior to and following continuous TBS (cTBS), intermittent TBS (iTBS), intermediate TBS (imTBS), and sham stimulation. Our results demonstrate that all active TBS paradigms significantly diminished the amplitude of the N2 component, when the hand contralateral to the site of TBS was laser-stimulated. Sham stimulation condition had no significant effect. The subjective pain perception also decreased during the experimental sessions, but did not differ significantly from the sham stimulation condition. The main finding of our study is that TBS over SI diminished the amplitude of the N2 component evoked from the contralateral side without any significant analgesic effects. Furthermore, imTBS produced responses similar to those observed by other forms of TBS induced excitability changes in the SI

Transcranial direct current stimulation disrupts tactile perception

Rogalewski A, Breitenstein C, Nitsche MA, Paulus W, Knecht S. Transcranial direct current stimulation disrupts tactile perception. European Journal of Neuroscience. 2004;20(1):313-316.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

Ein verlängertes Therapiefenster des Granulozyten Kolonie-stimulierenden Faktors im fokalen Ischämiemodell der Ratte

Minnerup J, Wysocki R, Laage R, Rogalewski A, Schneider A, Schäbitz W-R. Ein verlängertes Therapiefenster des Granulozyten Kolonie-stimulierenden Faktors im fokalen Ischämiemodell der Ratte. In: Abstracts Freier Vorträge und Poster der Jahrestagung der Deutschen Gesellschaft für Neurologie (DGN) Berlin, 12.-15. 9. 2007. Aktuelle Neurologie. Vol 34. Georg Thieme; 2007

Sex-Specific Differences in Octagenarian Stroke Patients Receiving Thrombolysis

Schäbitz M, Klein N, Wulff L, et al. Sex-Specific Differences in Octagenarian Stroke Patients Receiving Thrombolysis. In: ESOC 2022 Abstract Book. European Stroke Journal. Vol 7. Sage; 2022: 123

Discrepancy between theoretical knowledge and real action in acute stroke: self-assessment as an important predictor of time to admission

Ritter MA, Brach S, Rogalewski A, et al. Discrepancy between theoretical knowledge and real action in acute stroke: self-assessment as an important predictor of time to admission. Neurological Research. 2013;29(5):476-479.Background: Poor knowledge of stroke symptoms within the general population might be responsible for significant delay between symptom onset and hospital admission in most stroke patients. Methods: We prospectively evaluated whether theoretical knowledge about stroke influenced time to admission among 102 consecutive acute stroke patients using standardized questionnaires. We assessed in multiple logistic regression models the influence of theoretical knowledge (knowledge about stroke symptoms and knowledge about the appropriate actions to be taken in the case of a stroke) on the real actions taken in the acute situation. Predictors of a delayed hospital admission greater than 2 hours after stroke onset were determined. Models were adjusted for age, gender, level of education, stroke severity, previous history of stroke or transient ischemic attack (TIA), and being alone at symptom onset. Results: Patients arrived significantly later, if the patients themselves were the managers of the emergency situation [odds ratio (OR): 4.7; 95% confidence interval (CI): 1.5–140.8]. Symptom knowledge and action knowledge were not found to be significantly associated with shorter pre-hospital times, whereas the correct diagnosis of stroke by the manager (OR: 0.2; 95% CI: 0.1–0.4) and calling the emergency medical system (OR: 0.3; 95% CI: 0.1–0.7) independently led to a higher likelihood to arrive at a hospital within 2 hours. Conclusion: Our study underscores that good theoretical knowledge about stroke does not imply appropriate management in the emergency situation. Educational efforts need to incorporate more practical aspects in order to translate theoretical knowledge into concrete action

Repetitive TMS temporarily alters brain diffusion

Duning T, Rogalewski A, Steinstraeter O, et al. Repetitive TMS temporarily alters brain diffusion. Neurology. 2004;62(11):2144-2145