Safety and efficacy of Cerebrolysin in motor function recovery after stroke: a meta-analysis of the CARS trials.

This meta-analysis combines the results of two identical stroke studies (CARS-1 and CARS-2) assessing efficacy of Cerebrolysin on motor recovery during early rehabilitation. Cerebrolysin is a parenterally administered neuropeptide preparation approved for the treatment of stroke. Both studies had a prospective, randomized, double-blind, placebo-controlled design. Treatment with 30 ml Cerebrolysin once daily for 3 weeks was started 24-72 h after stroke onset. In addition, patients participated in a standardized rehabilitation program for 21 days that was initiated within 72 h after stroke onset. For both studies, the original analysis data were used for meta-analysis (individual patient data analysis). The combination of these two studies by meta-analytic procedures was pre-planned, and the methods were pre-defined under blinded conditions. The nonparametric Mann-Whitney (MW) effect size of the two studies on the ARAT score on day 90 indicated superiority of Cerebrolysin compared with placebo (MW 0.62, P < 0.0001, Wei-Lachin pooling procedure, day 90, last observation carried forward; N = 442). Also, analysis of early benefit at day 14 and day 21 by means of the National Institutes of Health Stroke Scale, which is regarded as most sensitive to early improvements, showed statistical significance (MW 0.59, P < 0.002). The corresponding number-needed-to-treat (NNT) for clinically relevant changes in early NIHSS was 7.1 (95% CI: 4 to 22). Cerebrolysin had a beneficial effect on motor function and neurological status in early rehabilitation patients after acute ischemic stroke. Safety aspects were comparable to placebo, showing a favourable benefit/risk ratio.

Cerebrolysin and Recovery After Stroke (CARS): A Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial.

BACKGROUND AND PURPOSE: The aim of this trial was to investigate whether stroke patients who receive Cerebrolysin show improved motor function in the upper extremities at day 90 compared with patients who receive a placebo. METHODS: This study was a prospective, randomized, double-blind, placebo-controlled, multicenter, parallel-group study. Patients were treated with Cerebrolysin (30 mL/d) or a placebo (saline) once daily for 21 days, beginning at 24 to 72 hours after stroke onset. The patients also participated in a standardized rehabilitation program for 21 days that was initiated within 72 hours after stroke onset. The primary end point was the Action Research Arm Test score on day 90. RESULTS: The nonparametric effect size on the Action Research Arm Test score on day 90 indicated a large superiority of Cerebrolysin compared with the placebo (Mann-Whitney estimator, 0.71; 95% confidence interval, 0.63-0.79; P<0.0001). The multivariate effect size on global status, as assessed using 12 different outcome scales, indicated a small-to-medium superiority of Cerebrolysin (Mann-Whitney estimator, 0.62; 95% confidence interval, 0.58-0.65; P<0.0001). The rate of premature discontinuation was <5% (3.8%). Cerebrolysin was safe and well tolerated. CONCLUSIONS: Cerebrolysin had a beneficial effect on function and global outcome in early rehabilitation patients after stroke. Its safety was comparable with that of the placebo, suggesting a favorable benefit/risk ratio. Because this study was exploratory and had a relatively small sample size, the results should be confirmed in a large-scale, randomized clinical trial. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrialsregister.eu. Unique identifier: 2007-000870-21.

National plans and awareness campaigns as priorities for achieving global brain health.

Neurological conditions are the leading cause of death and disability combined. This public health crisis has become a global priority with the introduction of WHO's Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders 2022-2031 (IGAP). 18 months after this plan was adopted, global neurology stakeholders, including representatives of the OneNeurology Partnership (a consortium uniting global neurology organisations), take stock and advocate for urgent acceleration of IGAP implementation. Drawing on lessons from relevant global health contexts, this Health Policy identifies two priority IGAP targets to expedite national delivery of the entire 10-year plan: namely, to update national policies and plans, and to create awareness campaigns and advocacy programmes for neurological conditions and brain health. To ensure rapid attainment of the identified priority targets, six strategic drivers are proposed: universal community awareness, integrated neurology approaches, intersectoral governance, regionally coordinated IGAP domestication, lived experience-informed policy making, and neurological mainstreaming (advocating to embed brain health into broader policy agendas). Contextualised with globally emerging IGAP-directed efforts and key considerations for intersectoral policy design, this novel framework provides actionable recommendations for policy makers and IGAP implementation partners. Timely, synergistic pursuit of the six drivers might aid WHO member states in cultivating public awareness and policy structures required for successful intersectoral roll-out of IGAP by 2031, paving the way towards brain health for all.

Global synergistic actions to improve brain health for human development.

The global burden of neurological disorders is substantial and increasing, especially in low-resource settings. The current increased global interest in brain health and its impact on population wellbeing and economic growth, highlighted in the World Health Organization's new Intersectoral Global Action Plan on Epilepsy and other Neurological Disorders 2022-2031, presents an opportunity to rethink the delivery of neurological services. In this Perspective, we highlight the global burden of neurological disorders and propose pragmatic solutions to enhance neurological health, with an emphasis on building global synergies and fostering a 'neurological revolution' across four key pillars - surveillance, prevention, acute care and rehabilitation - termed the neurological quadrangle. Innovative strategies for achieving this transformation include the recognition and promotion of holistic, spiritual and planetary health. These strategies can be deployed through co-design and co-implementation to create equitable and inclusive access to services for the promotion, protection and recovery of neurological health in all human populations across the life course.

Neurobiological foundations of neurologic music therapy: rhythmic entrainment and the motor system.

Entrainment is defined by a temporal locking process in which one system's motion or signal frequency entrains the frequency of another system. This process is a universal phenomenon that can be observed in physical (e.g., pendulum clocks) and biological systems (e.g., fire flies). However, entrainment can also be observed between human sensory and motor systems. The function of rhythmic entrainment in rehabilitative training and learning was established for the first time by Thaut and colleagues in several research studies in the early 1990s. It was shown that the inherent periodicity of auditory rhythmic patterns could entrain movement patterns in patients with movement disorders (see for a review: Thaut et al., 1999). Physiological, kinematic, and behavioral movement analysis showed very quickly that entrainment cues not only changed the timing of movement but also improved spatial and force parameters. Mathematical models have shown that anticipatory rhythmic templates as critical time constraints can result in the complete specification of the dynamics of a movement over the entire movement cycle, thereby optimizing motor planning and execution. Furthermore, temporal rhythmic entrainment has been successfully extended into applications in cognitive rehabilitation and speech and language rehabilitation, and thus become one of the major neurological mechanisms linking music and rhythm to brain rehabilitation. These findings provided a scientific basis for the development of neurologic music therapy.

Music mnemonics aid Verbal Memory and Induce Learning - Related Brain Plasticity in Multiple Sclerosis.

Recent research on music and brain function has suggested that the temporal pattern structure in music and rhythm can enhance cognitive functions. To further elucidate this question specifically for memory, we investigated if a musical template can enhance verbal learning in patients with multiple sclerosis (MS) and if music-assisted learning will also influence short-term, system-level brain plasticity. We measured systems-level brain activity with oscillatory network synchronization during music-assisted learning. Specifically, we measured the spectral power of 128-channel electroencephalogram (EEG) in alpha and beta frequency bands in 54 patients with MS. The study sample was randomly divided into two groups, either hearing a spoken or a musical (sung) presentation of Rey's auditory verbal learning test. We defined the "learning-related synchronization" (LRS) as the percent change in EEG spectral power from the first time the word was presented to the average of the subsequent word encoding trials. LRS differed significantly between the music and the spoken conditions in low alpha and upper beta bands. Patients in the music condition showed overall better word memory and better word order memory and stronger bilateral frontal alpha LRS than patients in the spoken condition. The evidence suggests that a musical mnemonic recruits stronger oscillatory network synchronization in prefrontal areas in MS patients during word learning. It is suggested that the temporal structure implicit in musical stimuli enhances "deep encoding" during verbal learning and sharpens the timing of neural dynamics in brain networks degraded by demyelination in MS.