The study of botulinum neurotoxins (BoNT) is rapidly progressing in many aspects. Novel BoNTs are being discovered owing to next generation sequencing, but their biologic and pharmacological properties remain largely unknown. The molecular structure of the large protein complexes that the toxin forms with accessory proteins, which are included in some BoNT type A1 and B1 pharmacological preparations, have been determined. By far the largest effort has been dedicated to the testing and validation of BoNTs as therapeutic agents in an ever increasing number of applications, including pain therapy. BoNT type A1 has been also exploited in a variety of cosmetic treatments, alone or in combination with other agents, and this specific market has reached the size of the one dedicated to the treatment of medical syndromes. The pharmacological properties and mode of action of BoNTs have shed light on general principles of neuronal transport and protein-protein interactions and are stimulating basic science studies. Moreover, the wide array of BoNTs discovered and to be discovered and the production of recombinant BoNTs endowed with specific properties suggest novel uses in therapeutics with increasing disease/symptom specifity. These recent developments are reviewed here to provide an updated picture of the biologic mechanism of action of BoNTs, of their increasing use in pharmacology and in cosmetics, and of their toxicology.

https://pharmrev.aspetjournals.org/content/pharmrev/69/2/200.full.pdf

Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology.

Schoenfeld, BJ, Grgic, J, Ogborn, D, and Krieger, JW. Strength and hypertrophy adaptations between low- vs. high-load resistance training: a systematic review and meta-analysis. J Strength Cond Res 31(12): 3508-3523, 2017-The purpose of this article was to conduct a systematic review of the current body of literature and a meta-analysis to compare changes in strength and hypertrophy between low- vs. high-load resistance training protocols. Searches of PubMed/MEDLINE, Cochrane Library, and Scopus were conducted for studies that met the following criteria: (a) an experimental trial involving both low-load training [≤60% 1 repetition maximum (1RM)] and high-load training (>60% 1RM); (b) with all sets in the training protocols being performed to momentary muscular failure; (c) at least one method of estimating changes in muscle mass or dynamic, isometric, or isokinetic strength was used; (d) the training protocol lasted for a minimum of 6 weeks; (e) the study involved participants with no known medical conditions or injuries impairing training capacity. A total of 21 studies were ultimately included for analysis. Gains in 1RM strength were significantly greater in favor of high- vs. low-load training, whereas no significant differences were found for isometric strength between conditions. Changes in measures of muscle hypertrophy were similar between conditions. The findings indicate that maximal strength benefits are obtained from the use of heavy loads while muscle hypertrophy can be equally achieved across a spectrum of loading ranges.

Strength and Hypertrophy Adaptations Between Low- vs. High-Load Resistance Training: A Systematic Review and Meta-analysis.

It has become common practice to incorporate balance tasks into the training program for athletes who want to improve performance and prevent injuries, in rehabilitation programs, and in fall prevention programs for the elderly. However, it is still unclear whether incorporating balance tasks into a training program increases performance only in these specific tasks or if it affects balance in a more general way. The objective of this systematic literature review and meta-analysis was to determine to what extent the training of balance tasks can improve performance in non-trained balance tasks. A systematic literature search was performed in the online databases EMBASE, PubMed, SPORTDiscus and Web of Science. Articles related to balance training and testing in healthy populations published between January 1985 and March 2015 were considered. A total of 3093 articles were systematically evaluated. Randomized controlled trials were included that (i) used only balance tasks during the training, (ii) used at least two balance tests before and after training, and (iii) tested performance in the trained balance tasks and at least one non-trained balance task. Six studies with a total of 102 subjects met these criteria and were included into the meta-analysis. The quality of the studies was evaluated by means of the Physiotherapy Evidence Database (PEDro) scale. A random effect model was used to calculate the between-subject standardized mean differences (SMDbs) in order to quantify the effect of balance training on various kinds of balance measures relative to controls. The tested balance tasks in each study were classified into tasks that had been trained and tasks that had not been trained. For further analyses, the non-trained balance tasks were subdivided into tasks with similar or non-similar body position and similar or non-similar balance perturbation direction compared to the trained task. The effect of balance training on the performance of the trained balance tasks reached an SMDbs of 0.79 [95 % confidence interval (CI) 0.48–1.10], indicating a high effect in favor for the trained task, with no notable heterogeneity (I
 2 = 0 %). The SMDbs in non-trained categories reached values between −0.07 (95 % CI −0.53 to 0.38) and 0.18 (95 % CI −0.27 to 0.64), with non-notable to moderate heterogeneity (I
 2 = 0–32 %), indicating no effect of the balance training on the respective non-trained balance tasks. With six studies, the number of studies included in this meta-analysis is rather low. It remains unclear how the limited number of studies with considerable methodological diversity affects the outcome of the SMD calculations and thus the general outcome of the meta-analysis. In healthy populations, balance training can improve the performance in trained tasks, but may have only minor or no effects on non-trained tasks. Consequently, therapists and coaches should identify exactly those tasks that need improvement, and use these tasks in the training program and as a part of the test battery that evaluates the efficacy of the training program. Generic balance tasks—such as one-leg stance—may have little value as overall balance measures or when assessing the efficacy of specific training interventions.

Specificity of Balance Training in Healthy Individuals: A Systematic Review and Meta-Analysis.

The striking differences between the clinical symptoms of tetanus and botulism have been ascribed to the different fate of the parental neurotoxins once internalised in motor neurons. Tetanus toxin (TeNT) is known to undergo transcytosis into inhibitory interneurons and block the release of inhibitory neurotransmitters in the spinal cord, causing a spastic paralysis. In contrast, botulinum neurotoxins (BoNTs) block acetylcholine release at the neuromuscular junction, therefore inducing a flaccid paralysis. Whilst overt experimental evidence supports the sorting of TeNT to the axonal retrograde transport pathway, recent findings challenge the established view that BoNT trafficking is restricted to the neuromuscular junction by highlighting central effects caused by these neurotoxins. These results suggest a more complex scenario whereby BoNTs also engage long-range trafficking mechanisms. However, the intracellular pathways underlying this process remain unclear. We sought to fill this gap by using primary motor neurons either in mass culture or differentiated in microfluidic devices to directly monitor the endocytosis and axonal transport of full length BoNT/A and BoNT/E and their recombinant binding fragments. We show that BoNT/A and BoNT/E are internalised by spinal cord motor neurons and undergo fast axonal retrograde transport. BoNT/A and BoNT/E are internalised in non-acidic axonal carriers that partially overlap with those containing TeNT, following a process that is largely independent of stimulated synaptic vesicle endo-exocytosis. Following intramuscular injection in vivo, BoNT/A and TeNT displayed central effects with a similar time course. Central actions paralleled the peripheral spastic paralysis for TeNT, but lagged behind the onset of flaccid paralysis for BoNT/A. These results suggest that the fast axonal retrograde transport compartment is composed of multifunctional trafficking organelles orchestrating the simultaneous transfer of diverse cargoes from nerve terminals to the soma, and represents a general gateway for the delivery of virulence factors and pathogens to the central nervous system.

/pdf/botulinum-neurotoxins-a-and-e-undergo-retrograde-axonal-1hc86wjbbd.pdf

Botulinum Neurotoxins A and E Undergo Retrograde Axonal Transport in Primary Motor Neurons

Balance training is considered an important means to decrease fall rates in seniors. Whether virtual reality training (VRT) might serve as an appropriate treatment strategy to improve neuromuscular fall risk parameters in comparison to alternative balance training programs (AT) is as yet unclear. To examine and classify the effects of VRT on fall-risk relevant balance performance and functional mobility compared to AT and an inactive control condition (CON) in healthy seniors. The literature search was conducted in five databases (CINAHL, EMBASE, ISI Web of Knowledge, PubMed, SPORTDiscus). The following search terms were used with Boolean conjunction: (exergam* OR exer-gam* OR videogam* OR video-gam* OR video-based OR computer-based OR Wii OR Nintendo OR X-box OR Kinect OR play-station OR playstation OR virtua* realit* OR dance dance revolution) AND (sport* OR train* OR exercis* OR intervent* OR balanc* OR strength OR coordina* OR motor control OR postur* OR power OR physical* OR activit* OR health* OR fall* risk OR prevent*) AND (old* OR elder* OR senior*). Randomized and non-randomized controlled trials applying VRT as interventions focusing on improving standing balance performance (single and double leg stance with closed and open eyes, functional reach test) and functional mobility (Berg balance scale, Timed-up and go test, Tinetti test) in healthy community-dwelling seniors of at least 60 years of age were screened for eligibility. Eligibility and study quality (PEDro scale) were independently assessed by two researchers. Standardized mean differences (SMDs) served as main outcomes for the comparisons of VRT versus CON and VRT versus AT on balance performance and functional mobility indices. Statistical analyses were conducted using a random effects inverse-variance model. Eighteen trials (mean PEDro score: 6 ± 2) with 619 healthy community dwellers were included. The mean age of participants was 76 ± 5 years. Meaningful effects in favor of VRT compared to CON were found for balance performance [p < 0.001, SMD: 0.77 (95 % CI 0.45–1.09)] and functional mobility [p = 0.004, SMD: 0.56 (95 % CI 0.25–0.78)]. Small overall effects in favor of AT compared to VRT were found for standing balance performance [p = 0.31, SMD: −0.35 (95 % CI −1.03 to 0.32)] and functional mobility [p = 0.05, SMD: −0.44 (95 % CI: −0.87 to 0.00)]. Sensitivity analyses between “weaker” (n = 9, PEDro ≤5) and “stronger” (n = 9, PEDro ≥6) studies indicated that weaker studies showed larger effects in favor of VRT compared to CON regarding balance performance (p < 0.001). Although slightly less effective than AT, VRT-based balance training is an acceptable method for improving balance performance as well as functional mobility outcomes in healthy community dwellers. VRT might serve as an attractive complementary training approach for the elderly. However, more high-quality research is needed in order to derive valid VRT recommendations compared to both AT and CON.

Effects of Virtual Reality Training (Exergaming) Compared to Alternative Exercise Training and Passive Control on Standing Balance and Functional Mobility in Healthy Community-Dwelling Seniors: A Meta-Analytical Review.

Task-specificity of balance training

The natural target of the botulinum neurototoxin type A (BoNT-A) is the neuromuscular junction When injected into a muscle, BoNT-A is internalized by motoneurone terminals where it functions as an endopeptidase, cleaving protein components of the synaptic machinery responsible for vesicle docking and exocytosis As a result, BoNT-A induces a characteristic flaccid paralysis of the affected muscle In animal models, BoNT-A applied in the periphery can also influence central activity via retrograde transport and transcytosis An analogous direct central effect in humans is still debated The present study was designed to address whether BoNT-A modifies the activity of the spinal recurrent inhibitory pathways, when injected at muscular level, in humans To avoid methodological bias, the recurrent inhibition from an injected muscle (soleus) was investigated on an untreated muscle (quadriceps), and stimulation parameters (producing recurrent inhibition) were monitored on a third non-injected muscle but innervated by the same nerve as the soleus (flexor digitorum brevis) The experiments were performed on 14 post-stroke patients exhibiting spasticity in ankle plantarflexors, candidates for BoNT-A One month after BoNT-A, the level of recurrent inhibition was depressed It is suggested that the depression of recurrent inhibition was induced by BoNT-A, injected peripherally, through axonal transport and blockade of the cholinergic synapse between motoneurone recurrent collaterals and Renshaw cells

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.2012.239178

Beyond muscular effects: depression of spinal recurrent inhibition after botulinum neurotoxin A.

Two independent lines of research propose that exertion of mental effort can impair subsequent performance due to ego depletion or mental fatigue. In this meta-analysis, we unite these research fields to facilitate a greater exchange between the two, to summarize the extant literature and to highlight open questions. We performed a meta-analysis to quantify the effect of ego-depletion and mental fatigue on subsequent physical endurance performance (42 independent effect sizes). We found that ego-depletion or mental fatigue leads to a reduction in subsequent physical endurance performance (ES = -0.506 [95% CI: -0.649, -0.369]) and that the duration of prior mental effort exertion did not predict the magnitude of subsequent performance impairment (r = -0.043). Further, analyses revealed that effects of prior mental exertion are more pronounced in subsequent tasks that use isolation tasks (e.g., handgrip; ES = -0.719 [-0.946, -0.493]) compared to whole-body endurance tasks (e.g. cycling; coefficient = 0.338 [0.057, 0.621]) and that the observed reduction in performance is higher when the person-situation fit is low (ES for high person-situation fit = -0.355 [-0.529, -0.181], coefficient for low person-situation fit = -0.336 [-0.599, -0.073]). Taken together, the aggregate of the published literature on ego depletion or mental fatigue indicates that prior mental exertion is detrimental to subsequent physical endurance performance. However, this analysis also highlights several open questions regarding the effects’ mechanisms and moderators. Particularly, the surprising finding that the duration of prior mental exertion seems to be unrelated to subsequent performance impairment needs to be addressed systematically.

/pdf/the-effect-of-ego-depletion-or-mental-fatigue-on-subsequent-2eq15w4ptb.pdf

The effect of ego depletion or mental fatigue on subsequent physical endurance performance : A meta-analysis

Aims
Different modalities of strength training cause performance enhancements, which are specific for the trained task. However, the involved mechanisms are still largely unknown. It has been demonstrated that strength training could induce neuroplasticity, which might underlie the performance improvements during the first training sessions. Thus, we hypothesized to find task-specific neuroplasticity after a short-term strength training of two distinct strength tasks.

Methods
Young healthy male subjects were exposed to 4 sessions of either maximal isometric explosive (EXPL group, N = 9) or slow sustained (SUS group, N = 10) knee extensions. Pre- and post-training, we measured H-reflexes and motor evoked potentials (MEPs) in the vastus lateralis (VL) at the onset of both strength tasks.

Results
Pre- and post-training, H-reflexes remained unchanged in both groups. MEP areas were lower in the trained task in both groups and remained unchanged in the untrained task.

Conclusion
The present study demonstrated that short-term strength training induces specific neuroplasticity for the trained task only. The fact that MEPs were lower, but H-reflex amplitudes remained unchanged at the onset of the trained tasks suggests that strength training elicited neuroplasticity at supraspinal level that most likely reflect an improved task-specific corticospinal efficiency.

This article is protected by copyright. All rights reserved.

Louis-Solal Giboin

Papers

Specificity of Balance Training in Healthy Individuals: A Systematic Review and Meta-Analysis.

Task-specificity of balance training

Beyond muscular effects: depression of spinal recurrent inhibition after botulinum neurotoxin A.

The effect of ego depletion or mental fatigue on subsequent physical endurance performance : A meta-analysis

Neuroplasticity following short-term strength training occurs at supraspinal level and is specific for the trained task