Age-Related Dysfunction in Balance: A Comprehensive Review of Causes, Consequences, and Interventions.

This review delves into the multifaceted aspects of age-related balance changes, highlighting their prevalence, underlying causes, and the impact they have on the elderly population. Central to this discussion is the exploration of various physiological changes that occur with aging, such as alterations in the vestibular, visual, proprioceptive systems, and musculoskeletal degeneration. We examine the role of neurological disorders, cognitive decline, and medication side effects in exacerbating balance issues. The review underscores the significance of early detection and effective intervention strategies in mitigating the risks associated with balance problems, such as falls and reduced mobility. It discusses the effectiveness of diverse intervention strategies, including exercise programs, rehabilitation techniques, and technological advancements like virtual reality, wearable devices, and telemedicine. Additionally, the review stresses the importance of a holistic approach in managing balance disorders, encompassing medication review, addressing comorbidities, and environmental modifications. The paper also presents future research directions, emphasizing the need for a deeper understanding of the complex mechanisms underlying balance changes with aging and the potential of emerging technologies and interdisciplinary approaches in enhancing assessment and intervention methods. This comprehensive review aims to provide valuable insights for healthcare providers, researchers, and policymakers in developing targeted strategies to improve the quality of life and ensure the well-being of the aging population.

Muscle Synergy Plasticity in Motor Function Recovery After Stroke.

In certain neurological disorders such as stroke, the impairment of upper limb function significantly impacts daily life quality and necessitates enhanced neurological control. This poses a formidable challenge in the realm of rehabilitation due to its intricate nature. Moreover, the plasticity of muscle synergy proves advantageous in assessing the enhancement of motor function among stroke patients pre and post rehabilitation training intervention, owing to the modular control strategy of central nervous system. It also facilitates the investigation of long-term alterations in remodeling of muscle functional performance among patients undergoing clinical rehabilitation, aiming to establish correlations between changes in muscle synergies and stroke characteristics such as type, stage, and sites. In this study, a three-week rehabilitation monitoring experiment was conducted to assess the motor function of stroke patients at different stages of rehabilitation based on muscle synergy performance. Additionally, we aimed to investigate the correlation between clinical scale scores, rehabilitation stages, and synergy performance in order to provide a more comprehensive understanding of stroke patient recovery. The results of 7 healthy controls and 16 stroke patients showed that high-functioning patients were superior to low-functioning patients in terms of motor function plasticity towards healthy individuals. Moreover, there was a high positive correlation between muscle synergies and clinical scale scores in high-functioning patients, and the significance gradually emerged with treatment, highlighting the potential of muscle synergy plasticity as a valuable tool for monitoring rehabilitation progress. The potential of this study was also demonstrated for elucidating the physiological mechanisms underlying motor function reconstruction within the central nervous system, which is expected to promote the further application of muscle synergy in clinical assessment.

Hemorrhagic stroke-induced subtype of inflammatory reactive astrocytes disrupts blood-brain barrier.

Astrocytes undergo disease-specific transcriptomic changes upon brain injury. However, phenotypic changes of astrocytes and their functions remain unclear after hemorrhagic stroke. Here we reported hemorrhagic stroke induced a group of inflammatory reactive astrocytes with high expression of Gfap and Vimentin, as well as inflammation-related genes lipocalin-2 (Lcn2), Complement component 3 (C3), and Serpina3n. In addition, we demonstrated that depletion of microglia but not macrophages inhibited the expression of inflammation-related genes in inflammatory reactive astrocytes. RNA sequencing showed that blood-brain barrier (BBB) disruption-related gene matrix metalloproteinase-3 (MMP3) was highly upregulated in inflammatory reactive astrocytes. Pharmacological inhibition of MMP3 in astrocytes or specific deletion of astrocytic MMP3 reduced BBB disruption and improved neurological outcomes of hemorrhagic stroke mice. Our study demonstrated that hemorrhagic stroke induced a group of inflammatory reactive astrocytes that were actively involved in disrupting BBB through MMP3, highlighting a specific group of inflammatory reactive astrocytes as a critical driver for BBB disruption in neurological diseases.

Low-intensity focused ultrasound stimulation promotes stroke recovery via astrocytic HMGB1 and CAMK2N1 in mice.

BACKGROUND: Low-intensity focused ultrasound stimulation (LIFUS) has been developed to enhance neurological repair and remodelling during the late acute stage of ischaemic stroke in rodents. However, the cellular and molecular mechanisms of neurological repair and remodelling after LIFUS in ischaemic stroke are unclear. METHODS: Ultrasound stimulation was treated in adult male mice 7 days after transient middle cerebral artery occlusion. Angiogenesis was measured by laser speckle imaging and histological analyses. Electromyography and fibre photometry records were used for synaptogenesis. Brain atrophy volume and neurobehaviour were assessed 0-14 days after ischaemia. iTRAQ proteomic analysis was performed to explore the differentially expressed protein. scRNA-seq was used for subcluster analysis of astrocytes. Fluorescence in situ hybridisation and Western blot detected the expression of HMGB1 and CAMK2N1. RESULTS: Optimal ultrasound stimulation increased cerebral blood flow, and improved neurobehavioural outcomes in ischaemic mice (p<0.05). iTRAQ proteomic analysis revealed that the expression of HMGB1 increased and CAMK2N1 decreased in the ipsilateral hemisphere of the brain at 14 days after focal cerebral ischaemia with ultrasound treatment (p<0.05). scRNA-seq revealed that this expression pattern belonged to a subcluster of astrocytes after LIFUS in the ischaemic brain. LIFUS upregulated HMGB1 expression, accompanied by VEGFA elevation compared with the control group (p<0.05). Inhibition of HMGB1 expression in astrocytes decreased microvessels counts and cerebral blood flow (p<0.05). LIFUS reduced CAMK2N1 expression level, accompanied by increased extracellular calcium ions and glutamatergic synapses (p<0.05). CAMK2N1 overexpression in astrocytes decreased dendritic spines, and aggravated neurobehavioural outcomes (p<0.05). CONCLUSION: Our results demonstrated that LIFUS promoted angiogenesis and synaptogenesis after focal cerebral ischaemia by upregulating HMGB1 and downregulating CAMK2N1 in a subcluster of astrocytes, suggesting that LIFUS activated specific astrocyte subcluster could be a key target for ischaemic brain therapy.

A Generalized Cortico-Muscular-Cortical Network to Evaluate the Effects of Three-Week Brain Stimulation.

OBJECTIVE: Post-stroke transcranial magnetic stimulation (TMS) has gradually become a brain intervention to assist patients in the recovery of motor function. The long lasting regulatory of TMS may involve the coupling changes between cortex and muscles. However, the effects of multi-day TMS on motor recovery after stroke is unclear. METHODS: This study proposed to quantify the effects of three-week TMS on brain activity and muscles movement performance based on a generalized cortico-muscular-cortical network (gCMCN). The gCMCN-based features were further extracted and combined with the partial least squares (PLS) method to predict the Fugl-Meyer of upper extremity (FMUE) in stroke patients, thereby establishing an objective rehabilitation method that can evaluate the positive effects of continuous TMS on motor function. RESULTS: We found that the improvement of motor function after three-week TMS was significantly correlated with the complexity trend of information interaction between hemispheres and the intensity of corticomuscular coupling. In addition, the fitting coefficient ([Formula: see text]) for predicted and actual FMUE before and after TMS were 0.856 and 0.963, respectively, suggesting that the gCMCN-based measurement may be a promising method for evaluating the therapeutic effect of TMS. CONCLUSION: From the perspective of a novel brain-muscles network with dynamic contraction as the entry point, this work quantified TMS-induced connectivity differences while evaluating the potential efficacy of multi-day TMS. SIGNIFICANCE: It provides a unique insight for the further application of intervention therapy in the field of brain diseases.

CCL5 mediated astrocyte-T cell interaction disrupts blood-brain barrier in mice after hemorrhagic stroke.

The crosstalk between reactive astrocytes and infiltrated immune cells plays a critical role in maintaining blood-brain barrier (BBB) integrity. However, how astrocytes interact with immune cells and the effect of their interaction on BBB integrity after hemorrhagic stroke are still unclear. By performing RNA sequencing in astrocytes that were activated by interleukin-1α (IL-1α), tumor necrosis factor α (TNFα), and complement component 1q (C1q) treatment, we found CCL5 was among the top upregulated genes. Immunostaining and western blot results demonstrated that CCL5 was increased in mice brain after hemorrhagic stroke. Flow cytometry showed that knockout of astrocytic CCL5 reduced the infiltration of CD8+ but not CD4+ T and myeloid cells into the brain (p < 0.05). In addition, knockout CCL5 in astrocytes increased tight junction-related proteins ZO-1 and Occludin expression; reduced Evans blue leakage, perforin and granzyme B expression; improved neurobehavioral outcomes in hemorrhagic stroke mice (p < 0.05), while transplantation of CD8+ T cells reversed these protective effects. Moreover, co-culture of CD8+ T cells with bEnd.3 cells induced the apoptosis of bEnd.3 cells, which was rescued by inhibiting perforin. In conclusion, our study suggests that CCL5 mediated crosstalk between astrocytes and CD8+ T cells represents an important therapeutic target for protecting BBB in stroke.

Differentiation in additive and multiplicative inputs to motoneuron pool as origins of spasticity - a neuromorphic modeling study.

Spasticity is characterized by a velocity-dependent increase in the tonic stretch reflex. Evidence suggests that spasticity originates from hyperactivity in the descending tract or reflex loop. To pinpoint the source of hyperactivity, however, is difficult due to lack of human data in-vivo. Thus, we implemented a neuromorphic model to revive the neurodynamics with spiking neuronal activity. Two types of input were modeled: (1) the additive condition (ADD) to apply tonic synaptic inputs directly into the reflex loop; (2) the multiplicative (MUL) condition to adjust the loop gains within the reflex loop. Results show that both conditions produced antagonist EMG responses resembling patient data. The timing of spasticity is more sensitive to the ADD condition, whereas the amplitude of spastic EMG is more sensitive to the MUL condition. In conclusion, our model shows that both additive and multiplicative hyperactivities suffice to elicit velocity-dependent spastic electromyographic signals (EMG), but with different sensitivities. This simulation study suggests that spasticity caused by different origins may be discernable by the progression of severity, which may help individualized goalsetting and parameter-selection in rehabilitation.Clinical Relevance-Potential application of neuromorphic modeling on spasticity includes selection of parameters for therapeutic plans, such as movement range, repetition, and load.

Advanced rehabilitation in ischaemic stroke research.

At present, due to the rapid progress of treatment technology in the acute phase of ischaemic stroke, the mortality of patients has been greatly reduced but the number of disabled survivors is increasing, and most of them are elderly patients. Physicians and rehabilitation therapists pay attention to develop all kinds of therapist techniques including physical therapy techniques, robot-assisted technology and artificial intelligence technology, and study the molecular, cellular or synergistic mechanisms of rehabilitation therapies to promote the effect of rehabilitation therapy. Here, we discussed different animal and in vitro models of ischaemic stroke for rehabilitation studies; the compound concept and technology of neurological rehabilitation; all kinds of biological mechanisms of physical therapy; the significance, assessment and efficacy of neurological rehabilitation; the application of brain-computer interface, rehabilitation robotic and non-invasive brain stimulation technology in stroke rehabilitation.

Adaptive designs for best treatment identification with top-two Thompson sampling and acceleration.

We consider outcome adaptive phase II or phase II/III trials to identify the best treatment for further development. Different from many other multi-arm multi-stage designs, we borrow approaches for the best arm identification in multi-armed bandit (MAB) approaches developed for machine learning and adapt them for clinical trial purposes. The best arm identification in MAB focuses on the error rate of identification at the end of the trial, but we are also interested in the cumulative benefit of trial patients, for example, the frequency of patients treated with the best treatment. In particular, we consider Top-Two Thompson Sampling (TTTS) and propose an acceleration approach for better performance in drug development scenarios in which the sample size is much smaller than that considered in machine learning applications. We also propose a variant of TTTS (TTTS2) which is simpler, easier for implementation, and has comparable performance in small sample settings. An extensive simulation study was conducted to evaluate the performance of the proposed approach in multiple typical scenarios in drug development.

Spatial correlated vortex arrays.

Spatial correlated vortex arrays may form in the same beam when a random source contains multiple helical phase structures. We introduced two types of partially coherent sources with Cartesian and polar symmetric helical phase structure and reveal the characteristics of their radiated fields, respectively. It is demonstrated that far fields generated by these families of sources carry interesting features through the joint regulation of coherence and topological charge, being lattice-like vortex patterns with adjustable dimension and shape.

Propensity score matching and stratification using multiparty data without pooling.

Matching and stratification based on confounding factors or propensity scores (PS) are powerful approaches for reducing confounding bias in indirect treatment comparisons. However, implementing these approaches requires pooled individual patient data (IPD). The research presented here was motivated by an indirect comparison between a single-armed trial in acute myeloid leukemia (AML), and two external AML registries with current treatments for a control. For confidentiality reasons, IPD cannot be pooled. Common approaches to adjusting confounding bias, such as PS matching or stratification, cannot be applied as 1) a model for PS, for example, a logistic model, cannot be fitted without pooling covariate data; 2) pooling response data may be necessary for some statistical inference (e.g., estimating the SE of mean difference of matched pairs) after PS matching. We propose a set of approaches that do not require pooling IPD, using a combination of methods including a linear discriminant for matching and stratification, and secure multiparty computation for estimation of within-pair sample variance and for calculations involving multiple control sources. The approaches only need to share aggregated data offline, rather than real-time secure data transfer, as required by typical secure multiparty computation for model fitting. For survival analysis, we propose an approach using restricted mean survival time. A simulation study was conducted to evaluate this approach in several scenarios, in particular, with a mixture of continuous and binary covariates. The results confirmed the robustness and efficiency of the proposed approach. A real data example is also provided for illustration.

Neural Mechanism Underlying Task-Specific Enhancement of Motor Learning by Concurrent Transcranial Direct Current Stimulation.

The optimal protocol for neuromodulation by transcranial direct current stimulation (tDCS) remains unclear. Using the rotarod paradigm, we found that mouse motor learning was enhanced by anodal tDCS (3.2 mA/cm2) during but not before or after the performance of a task. Dual-task experiments showed that motor learning enhancement was specific to the task accompanied by anodal tDCS. Studies using a mouse model of stroke induced by middle cerebral artery occlusion showed that concurrent anodal tDCS restored motor learning capability in a task-specific manner. Transcranial in vivo Ca2+ imaging further showed that anodal tDCS elevated and cathodal tDCS suppressed neuronal activity in the primary motor cortex (M1). Anodal tDCS specifically promoted the activity of task-related M1 neurons during task performance, suggesting that elevated Hebbian synaptic potentiation in task-activated circuits accounts for the motor learning enhancement. Thus, application of tDCS concurrent with the targeted behavioral dysfunction could be an effective approach to treating brain disorders.

Covalent Grafting of a Nickel Thiolate Catalyst onto Covalent Organic Frameworks for Increased Photocatalytic Activity.

Covalent organic frameworks (COFs) have recently emerged as prospective photoactive materials with noble Pt as a cocatalyst for photocatalytic hydrogen evolution. In this work, a series of SH-group-functionalized covalent organic frameworks, TpPa-1-SH-X, is prepared by reaction of p-phenylenediamine (Pa) and 1,3,5-triformylphloroglucinol (Tp) with p-NH2 C6 H4 SH as a modulating agent. The reaction of TpPa-1-SH-X with NiII acetylacetonate Ni(acac)2 gave nickel thiolate-immobilized TpPa-1 (TpPa-1-SNi-X). The highest hydrogen evolution rate was 10.87 mmol h-1 g-1 , which was an enhancement of 16.47, 3.83, and 1.84 times than that of the parent TpPa-1, covalent-bond-free [(p-NH2 C6 H4 S)2 Ni]n /TpPa-1-SH-10, and 3 wt % Pt-deposited TpPa-1, respectively. This enhanced photocatalytic hydrogen evolution is ascribed to enhanced crystallinity, the use of NiII thiolate as a cocatalyst and covalent bonding between the cocatalyst and TpPa-1.

Is Intention to Treat Still the Gold Standard or Should Health Technology Assessment Agencies Embrace a Broader Estimands Framework?: Insights and Perspectives From the National Institute for Health and Care Excellence and Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen on the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use E9 (R1) Addendum.

OBJECTIVES: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E9 (R1) addendum will have an important impact on the design and analysis of randomized controlled clinical trials, which represent crucial sources of evidence in health technology assessments, and on the intention-to-treat (ITT) principle in particular. This article brings together a task force of health economists and statisticians in academic institutes and the pharmaceutical industry, to examine the implications of the addendum from the perspective of the National Institute for Health and Care Excellence (NICE) and the Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) and to address the question of whether the ITT principle should be considered the gold standard for estimating treatment effects. METHODS: We review the ITT principle, as introduced in the ICH E9 guideline. We then present an overview of the ICH E9 (R1) addendum and its estimand framework, highlighting its premise and the proposed strategies for handling intercurrent events, and examine some cases among submissions to IQWiG and NICE. RESULTS: IQWiG and NICE appear to have diverging perspectives around the relevance of the ITT principle and, in particular, the acceptance of hypothetical strategies for estimating treatment effects, as suggested by examples where the sponsor proposed an alternative approach to the ITT principle when accounting for treatment switching for interventional oncology trials. CONCLUSIONS: The ICH E9 (R1) addendum supports the use of methods that depart from the ITT principle. The relevance of estimands using these methods depends on the perspectives and objectives of payers. It is challenging to design a study that meets all stakeholders' research questions. Different estimands may serve to answer different relevant questions or decision problems.

Random sources with rectangular coherence.

A convenient method for modeling partially coherent sources with rectangular coherence is introduced by structuring the degree of coherence as two separable arbitrary functions with arbitrary dependence of variables. The included examples have demonstrated new opportunities of modeling random sources for beam shaping applications by coherence modulation. The first example discusses a class of rectangular sinc-correlated models generating radiating fields with self-focusing features. As a second example, we introduce a new type of partially coherent vortex beams, which has a unique feature of self-rotation around the optical axis upon propagation.

Improving the performance of Bayesian logistic regression model with overdose control in oncology dose-finding studies.

An accurately identified maximum tolerated dose (MTD) serves as the cornerstone of successful subsequent phases in oncology drug development. Bayesian logistic regression model (BLRM) is a popular and versatile model-based dose-finding design. However, BLRM with original overdose control strategy has been reported to be safe but "excessively conservative." In this article, we investigate the reason for conservativeness and point out that a major reason could be the lack of appropriate underdose control. We propose designs that balance overdose and underdose control to improve the performance over the original BLRM. Simulation results reveal that the new designs have better accuracy and treat more patients at MTD.

A framework for quantifying the effects of transcranial magnetic stimulation on motor recovery from hemiparesis: corticomuscular network.

Objective. Transcranial magnetic stimulation (TMS) is an experimental therapy for promoting motor recovery from hemiparesis. At present, hemiparesis patients' responses to TMS are variable. To maximize its therapeutic potential, we need an approach that relates the electrophysiology of motor recovery and TMS. To this end, we propose corticomuscular network (CMN) representing the holistic motor system, including the cortico-cortical pathway, corticospinal tract, and muscle co-activation.Approach. CMN is made up of coherence between pairs of electrode signals and spatial locations of the electrodes. We associated coherence and graph features of CMN with Fugl-Meyer Assessment (FMA) for the upper extremity. Besides, we compared CMN between 8 patients with hemiparesis and 6 healthy controls and contrasted CMN of patients before and after a 1 Hz TMS.Main results. Corticomuscular coherence (CMC) correlated positively with FMA. The regression model between FMA and CMC between five pairs of channels had 0.99 adjusted and ap-value less than 0.01. Compared to healthy controls, CMN of patients tended to be a small-world network and was more interconnected with higher CMC. CMC between cortex and triceps brachii long head was higher in patients. 15 min 1 Hz TMS protocol induced coherence changes beyond the stimulation side and had a limited impact on CMN parameters that are related to motor recovery.Significance. CMN is a potential clinical approach to quantify rehabilitating progress. It also sheds light on the desirable electrophysiological effects of TMS based on which rehabilitating strategies can be optimized.

Upper Limb Motor Function Quantification in Post-Stroke Rehabilitation Using Muscle Synergy Space Model.

The muscle synergy hypothesis assumes that the nervous system controls muscles in groups to simplify behavioral tasks, which makes it possible for modularizing motor function assessment. This paper presents a new assessment method based on muscle synergy space (MSS) model to evaluate motor functions after stroke. It consists of spatiotemporal feature module, muscle activation module and synergy activation module, and focuses on the spatial and temporal characteristics of muscle synergies via synergy vectors and activation coefficients. We further applied this method to reveal spatial and temporal characteristics difference of muscle synergy between healthy controls and stroke patients. The effectiveness and accuracy of MSS model were proved by significant positive correlations between Fugl-Meyer score and the total number of optimal synergies of three modules. This measurement methodology could serve as a quantitative indicator for motor function and provide more scientific rehabilitation guidance.