Theta-burst stimulation as a therapeutic tool in neurological pathology: a systematic review.

TBS (theta-burst stimulation) is a novel therapeutic approach in a wide range of neurological diseases. The present systematic review aims to identify the various protocols used in the last years, to assess study quality and to offer a general overview of the current state of the literature. The systematic review was conducted according to the Preferred Reporting Item for Systematic Review and Meta-Analyses (PRISMA) guidelines. We applied the following inclusion criteria: (1) population over 18 years old with diagnosed neurological disorders, (2) patients treated with sessions of theta-burst stimulation, (3) randomized-controlled clinical trials, (4) articles in the English language, and (5) studies that report response and score reduction on a validated scale of the investigated disorder or remission rates. We included in the final analysis 56 randomized controlled trials focusing on different neurological pathologies (stroke, Parkinson`s disease, multiple sclerosis, tinnitus, dystonia, chronic pain, essential tremor and tic disorder), and we extracted data regarding study design, groups and comparators, sample sizes, type of coil, stimulation parameters (frequency, number of pulses, intensity, stimulation site etc.), number of sessions, follow-up, assessment through functional connectivity and neurological scales used. We observed a great interstudy heterogenicity that leads to a difficulty in drawing plain conclusions. TBS protocols have shown promising results in improving various symptoms in patients with neurological disorders, but larger and more coherent studies, using similar stimulation protocols and evaluation scales, are needed to establish guideline recommendations.

Cerebrolysin and repetitive transcranial magnetic stimulation (rTMS) in patients with traumatic brain injury: a three-arm randomized trial.

Introduction: Traumatic brain injury (TBI) is a major public health problem affecting millions worldwide. Despite significant advances in medical care, there are limited effective interventions for improving cognitive and functional outcomes in TBI patients. Methods: This randomized controlled trial investigated the safety and efficacy of combining repetitive transcranial magnetic stimulation (rTMS) and Cerebrolysin in improving cognitive and functional outcomes in TBI patients. Ninety-three patients with TBI were randomized to receive either Cerebrolysin and rTMS (CRB + rTMS), Cerebrolysin and sham stimulation (CRB + SHM), or placebo and sham stimulation (PLC + SHM). The primary outcome measures were the composite cognitive outcome scores at 3 and 6 months after TBI. Safety and tolerability were also assessed. Results: The study results demonstrated that the combined intervention of rTMS and Cerebrolysin was safe and well-tolerated by patients with TBI. Although no statistically significant differences were observed in the primary outcome measures, the descriptive trends in the study support existing literature on the efficacy and safety of rTMS and Cerebrolysin. Discussion: The findings of this study suggest that rTMS and Cerebrolysin may be effective interventions for improving cognitive and functional outcomes in TBI patients. However, limitations of the study, such as the small sample size and exclusion of specific patient populations, should be considered when interpreting the results. This study provides preliminary evidence for the safety and potential efficacy of combining rTMS and Cerebrolysin in improving cognitive and functional outcomes in TBI patients. The study highlights the importance of multidisciplinary approaches in TBI rehabilitation and the potential for combining neuropsychological measurements and interventions to optimize patient outcomes. Conclusion: Further research is needed to establish these findings' generalizability and identify the optimal dosages and treatment protocols for rTMS and Cerebrolysin.

Effects of N-Pep-12 dietary supplementation on neurorecovery after ischemic stroke.

BACKGROUND: The aim of the study was to evaluate the effects of N-Pep-12 dietary supplementation on neurorecovery of middle-aged and older adults with cognitive impairment after ischemic stroke, using neuropsychological outcome scales. METHODS: This was a pilot randomized-controlled, phase IV, academic clinical trial that aimed to assess the effect and the safety of a single daily dose of oral 90 mg of N-Pep-12 for 90 days in supporting neurorecovery, as compared with a control group, performed on middle-aged and older adults after supratentorial ischemic stroke. RESULTS: Study group differences in baseline changes at day 90 for Montreal Cognitive Assessment (MoCA), Hospital Anxiety and Depression Scale (HADS) - Anxiety subscale, Color Trails 1 and Symbol Search (number incorrect) were statistically significant (Mann-Whitney U test). For MoCA at day 90, a borderline 'intermediate effect' in favour of N-PEP-12 was observed (dCohen = 0.491, η2 = 0.057, OR = 2.436, p = 0.010). HADS Anxiety and Color Trails 1 at day 90 registered a 'small-to-intermediate' effect in favour of N-PEP-12 (dCohen = 0.424, η2 = 0.043, OR = 2.157, p = 0.026; dCohen = 0.481, η2 = 0.055, OR = 2.3927, p = 0.013, respectively). For symbol search errors, an 'intermediate' effect in favour of the control group was observed (dCohen = 0.501, η2 = 0.059, OR = 2.4811, p = 0.007). CONCLUSION: This exploratory clinical trial indicates a signal for the benefit of dietary supplementation with N-Pep-12 for the enhancement of neurorecovery after supratentorial ischemic stroke.

Cognitive function: holarchy or holacracy?

Cognition is the most complex function of the brain. When exploring the inner workings of cognitive processes, it is crucial to understand the complexity of the brain's dynamics. This paper aims to describe the integrated framework of the cognitive function, seen as the result of organization and interactions between several systems and subsystems. We briefly describe several organizational concepts, spanning from the reductionist hierarchical approach, up to the more dynamic theory of open complex systems. The homeostatic regulation of the mechanisms responsible for cognitive processes is showcased as a dynamic interplay between several anticorrelated mechanisms, which can be found at every level of the brain's organization, from molecular and cellular level to large-scale networks (e.g., excitation-inhibition, long-term plasticity-long-term depression, synchronization-desynchronization, segregation-integration, order-chaos). We support the hypothesis that cognitive function is the consequence of multiple network interactions, integrating intricate relationships between several systems, in addition to neural circuits.

The Effect of Cerebrolysin on the Predictive Value of Baseline Prognostic Risk Score in Moderate and Severe Traumatic Brain Injury.

Cognitive dysfunction is a significant complaint among patients after moderate to severe traumatic brain injury (TBI), with devastating consequences on functional recovery and quality of life. Prognostic models allow a better assessment and management of neurotrauma patients. The aim of the study was to demonstrate the predictive value of the Baseline Prognostic Risk Score (BPRS) in moderate to severe TBI, in a sample of patients treated with neurotrophic factors. Eighty patients with moderate-severe TBI from the CAPTAIN II study were included in secondary data analysis. Patients received active treatment with Cerebrolysin, 50 mL per day for ten days, followed by two treatment cycles with 10 mL per day for ten days. BPRS was determined on admission; the age was recorded, and patients were evaluated using the following neurocognitive tests: Mini-Mental State Essay (MMSE), Wechsler Adult Intelligence Scale-Third Edition Processing Speed Index (WAIS-III PSI) and Stroop Colour Word Test-Victoria Version at 10, 30 and 90 days. Hierarchical regression analysis was performed to investigate the unique predictive value of BPRS on cognitive evolution, independent of age. BPRS independently predicted scores on the WAIS-III PSI DSCales and the Word subscale of the Stroop Colour Word Test at 90 days. Age was a significant predictor for all the investigated scales at 10, 30, and 90 days. This study demonstrates the predictive value of a validated prognostic model (BPRS) for medium-term neurocognitive outcomes in a sample of moderate-severe traumatic brain injury treated with neurotrophic factors.

Efficacy and safety of cerebrolysin in neurorecovery after moderate-severe traumatic brain injury: results from the CAPTAIN II trial.

INTRODUCTION: The objective of this trial was to evaluate the efficacy and safety of Cerebrolysin in treating patients after moderate to severe traumatic brain injury (TBI) as an adjunct to standard care protocols. The trial was designed to investigate the clinical effects of Cerebrolysin in the acute (neuroprotective) stage and during early and long-term recovery as part of a neurorestorative strategy. MATERIALS AND METHODS: The study was a phase IIIb/IV single-center, prospective, randomized, double-blind, placebo-controlled clinical trial. Eligible patients with a Glasgow Coma Score (GCS) between 7 and 12 received study medication (50 ml of Cerebrolysin or physiological saline solution per day for 10 days, followed by two additional treatment cycles with 10 ml per day for 10 days) in addition to standard care. We tested ensembles of efficacy criteria for 90, 30, and 10 days after TBI with a priori ordered hypotheses using a multivariate, directional test, to reflect the global status of patients after TBI. RESULTS: The study enrolled 142 patients, of which 139 underwent formal analysis (mean age = 47.4, mean admission GCS = 10.4, and mean Baseline Prognostic Risk Score = 2.6). The primary endpoint, a multidimensional ensemble of 13 outcome scales, indicated a "small-to-medium"-sized effect in favor of Cerebrolysin, statistically significant at day 90 (MWcombined = 0.59, 95% CI 0.52 to 0.66, P = 0.0119). Safety and tolerability observations were comparable between treatment groups. CONCLUSION: Our trial confirms previous beneficial effects of the multimodal, biological agent Cerebrolysin for overall outcome after moderate to severe TBI, as measured by a multidimensional approach. Study findings must be appraised and aggregated in conjunction with existing literature, as to improve the overall level of insight regarding therapeutic options for TBI patients. The widely used pharmacologic intervention may benefit from a large-scale observational study to map its use and to establish comparative effectiveness in real-world clinical settings.

VaD - An Integrated Framework for Cognitive Rehabilitation.

BACKGROUND & OBJECTIVE: Vascular dementia is the second most common cause of dementia, with clinical features that depend on neural substrates affected by the vascular lesions. Like most neurological disorders, it involves alterations that range from the molecular level to neuronal networks. Such alterations begin as compensatory mechanisms that reshape every subsystem involved in the brain's homeostasis. Although there have been recent huge advances in understanding the pathophysiology of cognitive dysfunction, a suitable therapeutic approach to vascular dementia remains elusive. Pharmacological interventions have failed to sustainably improve cognitive function, and it is a well-known fact that there is a need to change the current view for providing neuroprotection and enhancing neurorecovery after stroke. Studies regarding cognitive training are also faced with the difficulty of drawing up protocols that can embrace a holistic approach in cognitively impaired patients. CONCLUSION: This review will present a brief synthesis of current results from basic research data and clinical studies regarding pharmacological and non-pharmacological interventions in vascular dementia and will offer an integrated view from the perspective of systems biology.