Contribution of ipsilesional versus contralesional pyramidal tract plasticity

Schlaganfall trägt zu erhöhter Mortalität und Morbidität trotz akut intensivmedizinischer Behandlung. Trotz vielversprechenden Ergebnisse von Seite der Akutbehandlung, die preklinische und klinische Versuche, die die Morbidität und Mortalität beim Schlaganfall in die postakute bis chronische Phase zu reduzieren versuchen, bleiben frustrierend. Nach dem Schlaganfall, das Hirnparenchym ist einem Reorganisationsprozess ausgesetzt indem vertiefte interzelluläre und zellulär-extrazelluläre Interaktionen eine wichtige Rolle spielen. Das Ontogenese Software wird „restarted“ und damit die endogene Plastizität nach dem Schlaganfall steigt. In wie fern wir diese Eigenschaft für therapeutische Zwecke „ausbeuten“ können bleibt bis jetzt unklar, allerdings man beobachtet bereits in viele Studien eine breitere Therapiefenster mit verlängertem Effekt und Erholungspotenzial nach dem Schlaganfall. In unserem Projekt haben wir mittels mehreren Readouts die Effekten von Erythropoietin (EPO) und Vascular endothelial growth factor (VEGF) auf die Neuroplastizität der langen Bahnen nach dem Schlaganfall untersucht. VEGF ist ein Wachstumsfaktor mit pleiotropen Effekte nach dem Schlaganfall und ist vor allem in die Astroglia und Mikroglia zusammen mit dem Rezeptoren VEGFR1 und VEGFR2 zu finden. In die akute Schlaganfall Phase VEGF ist für verschiedene Effekten in die Penumbra Region zuständig wie Förderung des neuronalen Überlebens, der Angiogenese Prozessen, der Proliferation von neuralen Stamzellen, deren Migration und Differenzierung. Anhalt neuen Studien wurde den VEGFR2 in den kontralesionalen Motorkortex nach dem Schlaganfall identifiziert . Diese Entdeckung weisst indirekt auf einer funktionelle Rolle der VEGF auf die kontralesionale Hemisphäre. Bis jetzt bleibt allerdings die Rolle der VEGF Therapie in die axonale Plastizität der langen Bahnen nach dem Schlaganfall unerforscht und dadurch auch seiner möglichen therapeutischen Rolle in die funktionelle Erholung. EPO ist ein Wachstumsfaktor mit einem breiten Spektrum der schon für klinische Verwendung zugelassen ist und damit zu einer schnelleren Translationsphase von preklinischen zu klinischen Experimenten geeignet ist. Die erste klinische Studie in der Erythropoietin nach dem Schlaganfall untersucht worden ist, zeigte eine Verbesserung der neurologischen Outcome mit Verkleinerung der ischämischen Schaden. In eine weitere Studie wurde dann der Effekt von EPO in 522 Patienten untersucht und zeigte dass die Verabreichung des EPO zusammen mit recombinant tissue-plasminogen activator (rt-PA) akut nach dem Schlaganfall zu einer signifikanten Nachblutung, Hirnödem und thromboembolische Ereignisse führte. Eine Falschinterpretation dieser Studie wird in die Zukunft für eine Ablehnung der EPO Therapie in Schlaganfall führen, obwohl eine alleinige Verabreichung des Epo eine Verbesserung zeigte. Unsere Studie untersucht die Effekte der Epo Therapie verabreicht drei Tage nach dem Schlaganfall mit Fokus auf die axonale Plastizität und funktionelle Erholung. Als Schlaganfall Model wurde eine 30 minutige Okklusion der A. cerebri media (MCAO) linkshemisphärisch durchgeführt. Die Verabreichung der Wachstumsfaktoren erfolgte am dritten postoperativen Tag mittels Alzet Pumpen die intraventrikulär implantiert wurden und eine kontinuierliche Verabreichung für verschiedene Zeitspannen gewährleistete. Als Kontrolle wurden die Pumpen mit NaCl 0.9% gefüllt und gemäss dem gleichen Protokoll intraventrikulär verabreicht. Sechs Wochen nach dem Schlaganfall und Therapie wurden die motorische Kortexanteile ipsi- und kontralesional mittels anterograden Tracttracers [Biotinyliertes Dextrane amid (BDA) in den kontralesionalen Motorkortex und Cascade Blue (CB) in den ipsilesionalen Motorkortex] markiert. Zwei Monate Postischämie wurden die Mäuse in Narkose getötet und das Gewebe für weitere molekularbiologische, biochemische, enzymologische, zytologische und genetische Untersuchungen verwendet. Die funktionelle Erholung als Korrelat zu Neurorehabilitation nach dem Schlaganfall wurde mittels RotaRod test, Grips strength test und Anxiety Test untersucht. Gemäss unseren Ergebnisse, VEGF und EPO Therapie verabreicht drei Tage nach dem Schlaganfall unterstützen die funktionelle Erholung durch koordinierte jedoch unterschiedliche Mechanismen die die Plastizität der langen Bahnen in der kontralesionalen Hemisphäre stimulieren. EPO zeigte vor allem eine vermehrte Translation der Plastizitätsgenen in der kontralesionalen Hemisphäre nach dem Schlaganfall die für eine erhöhte axonale Plastizität kontralesional verantwortlich waren. VEGF therapierten Tieren zeigten auch Erhöhung der axonalen Plastizität nach dem Schlaganfall kontralesional aber auf molekularer Ebene war das Effekt am besten durch eine Unterregulation von Plastizität hemmenden Substanzen in der Extrazellulären Matrix zu erklären.Stroke incidence is increasing due to the rapidly aging population in developed countries. Whereas untreated acute middle cerebral artery occlusion (MCAO) causes death in 20% of patients and long-term disability in more than 70% of patients, acute stroke therapy with rapid vessel recanalization significantly reduces mortality without influencing functional recovery beyond the acute stroke phase. This lack of functional recovery suggests a need for innovative therapies that can restore function after stroke. The purpose of these studies was to examine the effects of delayed administration of the growth factors erythropoietin (Epo) and vascular endogenous growth factor (VEGF) on functional neurological recovery and pyramidal tract plasticity in mice. The first study investigated how subacute delivery of Epo, starting at 3 days after stroke onset and continuing for 30 days (1 I.U. /day or 10 I.U. /day; via mini osmotic pump), influenced neuronal survival, axonal sprouting and neurological function recovery in C57Bl6/j mice submitted to 30-min MCAO. Epo administered in a 10 I.U. /day dose, in contrast to the 1 I.U. /day administration, showed a significant increase in neuronal survival and CD31 + newly-formed capillaries. This vascular growth enabled further neuroregeneration processes. Functional behavioral tests showed a significant improvement of motor coordination (RotaRod test) and grip strength (Grips strength test) among mice with 10 I.U. /day Epo administration, with no improvement for the low dose group. To investigate the neurological changes underlying these results, two anterograde tract tracers (dextrane amines) were injected in the motor cortex ipsilateral and contralateral to the ischemic lesion, in mice treated with the higher Epo dose. Histological evaluation of the tracers, both at the level of rubral and facial nucleus, showed that functional recovery in these animals was due to an increase of contralateral projections, accompanied by a compensatory decrease of ipsilateral projections. In the second study, VEGF was investigated due to its dual actions on vessels and neurons, which have potential for promoting long distance axonal plasticity in the ischemic brain. Mice were submitted to 30 minutes MCAO, followed by the intraventricular delivery of normal saline or VEGF (0.004 or 0.02 µg/day) starting 3 days post-ischemia. The outcome parameters were functional neurological recovery, long distance axonal plasticity by anterograde tract tracing and cellular and molecular responses examined by histochemistry, RT-PCR and Western blots. VEGF promoted neurological recovery when administered at the higher dosage, by stimulating long distance axonal plasticity in the contralesional but not ipsilesional pyramidal tract system. This observation was accompanied by deactivation of matrix metalloproteinase-9 (MMP9) in the ipsilesional brain tissue and downregulation of axonal growth inhibitors and guidance molecules in the contralesional brain tissue. The results support the concept that brain plasticity is consistent with coordinated axonal growth responses both ipsilateral and contralateral to the site of stroke. Considering that Epo is well tolerated in humans, clinical studies are now conceivable in which Epo is applied in patients in the post-acute stroke phase

Vascular endothelial growth factor induces contralesional corticobulbar plasticity and functional neurological recovery in the ischemic brain

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor, which also has neuroprotective activity. In view of these dual actions on vessels and neurons, we were interested whether VEGF promotes long distance axonal plasticity in the ischemic brain. Herein, we show that VEGF promotes neurological stroke recovery in mice when delivered in a delayed way starting 3 days after middle cerebral artery occlusion. Using anterograde tract-tracing experiments that we combined with histochemical and molecular biological studies, we demonstrate that although VEGF promoted angiogenesis predominantly in the ischemic hemisphere, pronounced axonal sprouting was induced by VEGF in the contralesional, but not the ipsilesional corticobulbar system. Corticobulbar plasticity was accompanied by the deactivation of the matrix metalloproteinase MMP9 in the lesioned hemisphere and the transient downregulation of the axonal growth inhibitors NG2 proteoglycan and brevican and the guidance molecules ephrin B1/2 in the contralesional hemisphere. The regulation of matrix proteinases, growth inhibitors, and guidance molecules offers insights how brain plasticity is controlled in the ischemic brain

Ultrasound Perfusion Imaging for the Detection of Cerebral Hypoperfusion After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND Delayed cerebral ischemia increases mortality and morbidity after aneurysmal subarachnoid hemorrhage (aSAH). Various techniques are applied to detect cerebral vasospasm and hypoperfusion. Contrast-enhanced ultrasound perfusion imaging (UPI) is able to detect cerebral hypoperfusion in acute ischemic stroke. This prospective study aimed to evaluate the use of UPI to enable detection of cerebral hypoperfusion after aSAH. METHODS We prospectively enrolled patients with aSAH and performed UPI examinations every second day after aneurysm closure. Perfusion of the basal ganglia was outlined to normalize the perfusion records of the anterior and posterior middle cerebral artery territory. We applied various models to characterize longitudinal perfusion alterations in patients with delayed ischemic neurologic deficit (DIND) across the cohort and predict DIND by using a multilayer classification model. RESULTS Between August 2013 and December 2015, we included 30 patients into this prospective study. The left-right difference of time to peak (TTP) values showed a significant increase at day 10-12. Patients with DIND demonstrated a significant, 4.86 times increase of the left-right TTP ratio compared with a mean fold change in patients without DIND of 0.9 times (p = 0.032). CONCLUSIONS UPI is feasible to enable detection of cerebral tissue hypoperfusion after aSAH, and the left-right difference of TTP values is the most indicative result of this finding

Development of a model to predict the probability of incurring a complication during spine surgery

PURPOSE Predictive models in spine surgery are of use in shared decision-making. This study sought to develop multivariable models to predict the probability of general and surgical perioperative complications of spinal surgery for lumbar degenerative diseases. METHODS Data came from EUROSPINE's Spine Tango Registry (1.2012-12.2017). Separate prediction models were built for surgical and general complications. Potential predictors included age, gender, previous spine surgery, additional pathology, BMI, smoking status, morbidity, prophylaxis, technology used, and the modified Mirza invasiveness index score. Complete case multiple logistic regression was used. Discrimination was assessed using area under the receiver operating characteristic curve (AUC) with 95% confidence intervals (CI). Plots were used to assess the calibration of the models. RESULTS Overall, 23'714/68'111 patients (54.6%) were available for complete case analysis: 763 (3.2%) had a general complication, with ASA score being strongly predictive (ASA-2 OR 1.6, 95% CI 1.20-2.12; ASA-3 OR 2.98, 95% CI 2.19-4.07; ASA-4 OR 5.62, 95% CI 3.04-10.41), while 2534 (10.7%) had a surgical complication, with previous surgery at the same level being an important predictor (OR 1.9, 95%CI 1.71-2.12). Respectively, model AUCs were 0.74 (95% CI, 0.72-0.76) and 0.64 (95% CI, 0.62-0.65), and calibration was good up to predicted probabilities of 0.30 and 0.25, respectively. CONCLUSION We developed two models to predict complications associated with spinal surgery. Surgical complications were predicted with less discriminative ability than general complications. Reoperation at the same level was strongly predictive of surgical complications and a higher ASA score, of general complications. A web-based prediction tool was developed at https://sst.webauthor.com/go/fx/run.cfm?fx=SSTCalculator

Development of the "Core Yellow Flags Index" (CYFI) as a brief instrument for the assessment of key psychological factors in patients undergoing spine surgery

Background: Depression, anxiety, catastrophising, and fear-avoidance beliefs are key "yellow flags" (YFs) that predict a poor outcome in back patients. Most surgeons acknowledge the importance of YFs but have difficulty assessing them due to the complexity of the instruments used for their measurement and time constraints during consultations. We performed a secondary analysis of existing questionnaire data to develop a brief tool to enable the systematic evaluation of YFs and then tested it in clinical practice. Methods: The following questionnaire datasets were available from a total of 932 secondary/tertiary care patients (61 ± 16 years; 51% female): pain catastrophising (N = 347); ZUNG depression (N = 453); Hospital Anxiety and Depression Scale (anxiety subscale) (N = 308); fear-avoidance beliefs (N = 761). The single item that best represented the full-scale score was identified, to form the 4-item "Core Yellow Flags Index" (CYFI). 2422 patients (64 ± 16 years; 54% female) completed CYFI and a Core Outcome Measures Index (COMI) before lumbar spine surgery, and a COMI 3 and 12 months later (FU). Results: The item-total correlation for each item with its full-length questionnaire was: 0.77 (catastrophising), 0.67 (depression), 0.69 (anxiety), 0.68 (fear-avoidance beliefs). Cronbach's α for the CYFI was 0.79. Structural equation modelling showed CYFI uniquely explained variance (p < 0.001) in COMI at both the 3- and 12-month FUs (β = 0.11 (women), 0.24 (men); and β = 0.13 (women), β = 0.14 (men), respectively). Conclusion: The 4-item CYFI proved to be a simple, practicable tool for routinely assessing key psychological attributes in spine surgery patients and made a relevant contribution in predicting postoperative outcome. CYFI's items were similar to those in the "STarT Back screening tool" used in primary care to triage patients into treatment pathways, further substantiating its validity. Wider use of CYFI may help improve the accuracy of predictive models derived using spine registry data. Keywords: Core Yellow Flags Index (CYFI); Outcome; Registry data; SPINE surgery; Yellow flags

HMG-CoA reductase inhibition promotes stroke recovery perilesional tissue remodeling and contralesional pyramidal tract plasticity

Joint Congress of European Neurology -- MAY 31-JUN 03, 2014 -- Istanbul, TURKEYWOS: 000347674000191…European Federation of Neurological Societie

HMG-CoA reductase inhibition promotes stroke recovery perilesional tissue remodeling and contralesional pyramidal tract plasticity

Joint Congress of European Neurology -- MAY 31-JUN 03, 2014 -- Istanbul, TURKEYWOS: 000337563600191…European Federation of Neurological Societie

Erratum to: Vascular endothelial growth factor induces contralesional corticobulbar plasticity and functional neurological recovery in the ischemic brain.

Erratum to: Acta Neuropathol (2012) 123:273–284. DOI 10.1007/s00401‑011‑0914‑z. The authors would like to correct Fig. 3 of the original manuscript, since the image in Fig. 3b does not correspond to a VEGF treated animal. Corrected Fig. 3 is shown below. We apologize for this mistake

Are large language models valid tools for patient information on lumbar disc herniation? The spine surgeons' perspective

Introduction: Generative AI is revolutionizing patient education in healthcare, particularly through chatbots that offer personalized, clear medical information. Reliability and accuracy are vital in AI-driven patient education. Research question: How effective are Large Language Models (LLM), such as ChatGPT and Google Bard, in delivering accurate and understandable patient education on lumbar disc herniation? Material and methods: Ten Frequently Asked Questions about lumbar disc herniation were selected from 133 questions and were submitted to three LLMs. Six experienced spine surgeons rated the responses on a scale from “excellent” to “unsatisfactory,” and evaluated the answers for exhaustiveness, clarity, empathy, and length. Statistical analysis involved Fleiss Kappa, Chi-square, and Friedman tests. Results: Out of the responses, 27.2% were excellent, 43.9% satisfactory with minimal clarification, 18.3% satisfactory with moderate clarification, and 10.6% unsatisfactory. There were no significant differences in overall ratings among the LLMs (p = 0.90); however, inter-rater reliability was not achieved, and large differences among raters were detected in the distribution of answer frequencies. Overall, ratings varied among the 10 answers (p = 0.043). The average ratings for exhaustiveness, clarity, empathy, and length were above 3.5/5. Discussion and conclusion: LLMs show potential in patient education for lumbar spine surgery, with generally positive feedback from evaluators. The new EU AI Act, enforcing strict regulation on AI systems, highlights the need for rigorous oversight in medical contexts. In the current study, the variability in evaluations and occasional inaccuracies underline the need for continuous improvement. Future research should involve more advanced models to enhance patient-physician communication