A tailored phytosomes based nose-to-brain drug delivery strategy: Silver bullet for Alzheimer's disease

 

This is in rats so your competent? doctor will need to contact non-existent stroke leadership to get human testing done. But that won't occur, will it?

A tailored phytosomes based nose-to-brain drug delivery strategy: Silver bullet for Alzheimer's disease

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https://doi.org/10.1016/j.bioactmat.2024.09.039

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Highlights

• •
  Designing a Ginseng RG3-based phytosomes for the delivery of rivastigmine hydrogen tartrate.
• •
  Proposing a nose-to-brain delivery strategy for bypassing the blood-brain barrier.
• •
  Providing a novel insight into the treatment of Alzheimer's disease.

Abstract

With the aging of the population, the incidence of Alzheimer's disease (AD) has increased dramatically, causing severe medical, care, and economic burdens on society and families. The efficacy of rivastigmine hydrogen tartrate (RHT), the first-line clinical treatment, is severely limited by the complex and multiple pathogenesis of AD and low brain bioavailability caused by the blood-brain barrier (BBB). Confronting such two bottlenecks, the development of multi-target agents encapsulated BBB-bypassing drug delivery systems offer tremendous therapeutics possibilities for AD. In this study, a tailored phytosomes based nose-to-brain drug delivery system with appropriate plume was successfully designed and developed. On the one hand, Ginseng RG3-based phytosomes loaded with RHT was designed for the co-delivery of GRg3 and RHT, achieving the multi-target pharmacology for AD treatment. On the other hand, a tailored nose-to-brain drug delivery system was established for the satisfactory nose-to-brain delivery efficiency, avoiding the obstacle of BBB through bypassing it. In the pharmacodynamic study based on AD rat model, GRg3@RHT exhibited obviously synergic effect, effectively break the vicious cycle of AD progression, ultimately markedly ameliorating learning and memory ability as well as behavioral dysfunctions, and delaying the neurodegenerative process associated with AD. In addition, the strong correlation of viscosity-droplet size-plume geometry-olfactory deposition was also established, and further proved by the in vivo pharmacokinetic study, which is proposed to provide evidence to enhance nose-to-brain delivery efficiency. This study is anticipated to provide novel insights into AD treatment strategies while offering innovative ideas for drug delivery approaches targeting nervous system disorders.

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Nose-to-brain delivery of stem cells in stroke: the role of extracellular vesicles

 

But why go thru all the trouble of stem cells if exosomes are the reason for the benefits? Which must be why no one seems to be monitoring stem cell survival.

Application of stem cell-derived exosomes in ischemic diseases: opportunity and limitations

The latest here:

Nose-to-brain delivery of stem cells in stroke: the role of extracellular vesicles

, , , , , 

Stem Cells Translational Medicine, szae072, https://doi.org/10.1093/stcltm/szae072

Published:

14 October 2024

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Abstract

Stem cell transplantation offers a promising therapy that can be administered days, weeks, or months after a stroke. We recognize 2 major mitigating factors that remain unresolved in cell therapy for stroke, notably: (1) well-defined donor stem cells and (2) mechanism of action. To this end, we advance the use of ProtheraCytes, a population of non-adherent CD34+ cells derived from human peripheral blood and umbilical cord blood, which have been processed under good manufacturing practice, with testing completed in a phase 2 clinical trial in post-acute myocardial infarction (NCT02669810). We also reveal a novel mechanism whereby ProtheraCytes secrete growth factors and extracellular vesicles (EVs) that are associated with angiogenesis and vasculogenesis. Our recent data revealed that intranasal transplantation of ProtheraCytes at 3 days after experimentally induced stroke in adult rats reduced stroke-induced behavioral deficits and histological damage up to 28 days post-stroke. Moreover, we detected upregulation of human CD63+ EVs in the ischemic brains of stroke animals that were transplanted with ProtheraCytes, which correlated with increased levels of DCX-labeled neurogenesis and VEGFR1-associated angiogenesis and vasculogenesis, as well as reduced Iba1-marked inflammation. Altogether, these findings overcome key laboratory-to-clinic translational hurdles, namely the identification of well-characterized, clinical grade ProtheraCytes and the elucidation of a potential CD63+ EV-mediated regenerative mechanism of action. We envision that additional translational studies will guide the development of clinical trials for intranasal ProtheraCytes allografts in stroke patients, with CD63 serving as a critical biomarker.

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Stem cells and extracellular vesicles (EVs). The release of CD-63-labeled EVs utilizes the pathway used by high density lipid biogenesis, that is, ApoA-1 cholesterol efflux. CD-63-labeled EVs are lipoprotein structures released from cells that may be enhanced by ApoA-1 involving gene fusion between the transmembrane protein CD-63 and a sequence from ApoA-1. Accordingly, ApoA-1 appears to serve as a receptor to CD63.

Radixin: Roles in the Nervous System and Beyond

 FYI. Someone is stroke leadership needs to assign this to a brilliant researcher to figure out if this can be used for stroke recovery. But since there is NO leadership in stroke; NOTHING WILL OCCUR!

Radixin: Roles in the Nervous System and Beyond            

                                 by

Zhao Zhong Chong

^1,* and

Nizar Souayah

^1,2,*

¹

Department of Neurology, New Jersey Medical School, Rutgers University, 185 S. Orange Ave, Newark, NJ 07103, USA

²

Department of Neurology, New Jersey Medical School, Rutgers University, 90 Bergen Street DOC 8100, Newark, NJ 07101, USA

^*

Authors to whom correspondence should be addressed.

Biomedicines 2024, 12(10), 2341; https://doi.org/10.3390/biomedicines12102341 (registering DOI)

Submission received: 16 September 2024 / Revised: 10 October 2024 / Accepted: 14 October 2024 / Published: 15 October 2024

(This article belongs to the Section Neurobiology and Clinical Neuroscience)

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Simple Summary

Radixin is a cytoskeletal-associated protein, a member of the ERM (ezrin, radixin, and moesin) protein family. Radixin plays important roles in cell shape, growth, and motility after activation by phosphorylation of its conserved threonine residues. Radixin functions as a relay in cell signaling pathways by binding to membrane proteins and transferring the cell signals into the cells. The pathogenic function of radixin has been found in central nervous system diseases, peripheral nerve injury, and cancers. We recently found significantly altered radixin in Schwann cells during elevated glucose, suggesting that it may be related to diabetes-induced nerve injury. As a result, the insight review into the roles of radixin and its associated cell signaling pathways may facilitate finding novel therapeutic targets for associated diseases.

Abstract

Background: Radixin is an ERM family protein that includes radixin, moesin, and ezrin. The importance of ERM family proteins has been attracting more attention, and studies on the roles of ERM in biological function and the pathogenesis of some diseases are accumulating. In particular, we have found that radixin is the most dramatically changed ERM protein in elevated glucose-treated Schwann cells. Method: We systemically review the literature on ERM, radixin in focus, and update the roles of radixin in regulating cell morphology, interaction, and cell signaling pathways. The potential of radixin as a therapeutic target in neurodegenerative diseases and cancer was also discussed. Results: Radixin research has focused on its cell functions, activation, and pathogenic roles in some diseases. Radixin and other ERM proteins maintain cell shape, growth, and motility. In the nervous system, radixin has been shown to prevent neurodegeration(This is good!) and axonal growth(Not clear; are we preventing or assisting axon growth?) . The activation of radixin is through phosphorylation of its conserved threonine residues. Radixin functions in cell signaling pathways by binding to membrane proteins and relaying the cell signals into the cells. Deficiency of radixin has been involved in the pathogenic process of diseases in the central nervous system and diabetic peripheral nerve injury. Moreover, radixin also plays a role in cell growth and drug resistance in multiple cancers. The trials of therapeutic potential through radixin modulation have been accumulating. However, the exact mechanisms underlying the roles of radixin are far from clarification. Conclusions: Radixin plays various roles in cells and is involved in developing neurodegenerative diseases and many types of cancers. Therefore, radixin may be considered a potential target for developing therapeutic strategies for its related diseases. Further elucidation of the function and the cell signaling pathways that are linked to radixin may open the avenue to finding novel therapeutic strategies for diseases in the nervous system and other body systems.

Keywords:

radixin; ERM; phosphorylation; neurodegeneration; peripheral nerve injury; cancer

1. Introduction

Radixin is one of the ERM family proteins, including ezrin, radixin, and moesin. ERM proteins, functioning as the link that bridges the actin cytoskeleton and membrane proteins, play very important roles in maintaining cell shape and motility through physically anchoring membrane proteins and assisting the signal transduction of post-translational processes [1]. ERMs also act as intracellular scaffolding proteins to relay the extracellular stimuli to the intracellular compartments of the cells [2]. In addition, ERMs have been demonstrated to regulate membrane dynamics and protrusion, cell adhesion, cell migration, and cell survival [2]. The broad cellular function of ERM implies that the deregulation of ERM holds potential roles in the development of diseases. In this article, we discussed the biological activity of ERM with a focus on radixin in a variety of diseases.

2. Activation of Radixin

2.1. Radixin Structure

The three ERM proteins possess similar structures, containing three major domains (Figure 1A,B). The amino terminus (N-terminus) is the four-point-one, ezrin, radixin, and moesin (FERM) domain that consists of F1, F2, and F3 subdomains (represented by A, B and C subdomains, respectively) [3]. The FERM domain, also named the N-terminal ERM-association domain (N-ERMAD), is the site for ERM proteins to interact with cell membranes. The FERM domain can bind to membranes, integral membrane proteins, and scaffolding proteins [4]. A central helical domain comprises three α helices, α1H, α2H, and α3H. α2H and α3H form a coiled-coil structure called the α-helical domain, while α1H acts as a linker region that connects the FERM domain and α-helical domain. The α-helical domain can bind to and mask the FERM domain. The carboxyl-terminal (C-terminal) end contains the F-actin binding domain, also known as the C-terminal ERM-association domain (C-ERMAD), which can bind the FERM domain and F-actin.

Figure 1. (A) Schematic ERM (ezrin, radixin, and moesin) protein domain structure. The N-terminus is the four-point-one, ezrin, radixin, moesin (FERM) domain that has F1, F2, and F3 subdomains. The FERM domain, also called N-terminal ERM association domain (N-ERMAD), is the site for ERM proteins to interact with the cell membrane. A central helical domain comprises three α helices, α1H, α2H, and α3H, which functions as a linker region connecting the FERM domain and an α-helical domain at the central portion of the protein. The α-helical domain can bind the FERM domain to facilitate the masking of both domains. The C-terminal end is the F-actin binding domain, also known as the C-terminal ERM-association domain (C-ERMAD), which has the ability to bind the FERM domain or F-actin. (B) The crystal structure of ERM proteins (reproduced from [3] and authorized by the publisher). (C) The inactive form of ERM proteins with C-ERMAD domain binding to and covering the FERM domain. (D) The active form of ERM proteins with the FERM domain released from the binding to the C-ERMAD domain.

2.2. Radixin Activation

While performing its biological activities, ERM changes its conformation from inactive to active. The two confirmations are inactive closed form and active open form. The FERM domain of ERM proteins is shut in an inactive state due to the interaction of the N-terminal end with the C-terminal regions [2]. As shown in Figure 1C, in the inactive closed conformation, the C-ERMAD domain binds and covers both the F-actin and N-ERMAD (FERM domain), masking interaction sites of the FERM domain and F domain, leading to the loss of their binding ability to the membrane proteins, cytoskeletal protein, and other adaptor proteins [5]. Further studies indicated that the central α-helix-rich domain and linker regions also interact with F1 and F2 of the FERM domain, contributing to the masking of the binding sites [6].

To release the FERM domain from intermolecular binding, phosphorylation of conserved residue, threonine (Thr), in the FERM domain is required. Thr phosphorylation disrupts the binding between the FERM domain and the C-ERMAD region, relieving the FERM domain from the intramolecular association (Figure 1D). The phosphorylation of radixin has been demonstrated to disrupt the binding to the N-terminal domain to recover the binding ability of FERM without affecting the F-actin binding site. Phosphorylation of ezrin and moesin simultaneously unmasks both the F-actin and FERM binding sites. Ezrin is activated through phosphorylation of Thr567 at the C-ERMAD domain [7], leading to attenuating the affinity of the FERM domain to the C-ERMAD and reopening the binding sites of F-actin. The equivalent phosphorylation sites of radixin and moesin are Thr564 and Thr558, respectively [8]. However, phosphorylation of C-terminal Thr573 of radixin is required for both F-actin binding and improves protein stability [9].

2.3. Kinases and Radixin Phosphorylation

Many cellular kinases can phosphorylate the residues in C-ERMAD domain (Table 1). G-protein coupled receptor kinase 2 (GRK2) phosphorylates ezrin on Thr567, and is involved in membrane protrusion and motility in epithelial cells [10] and in G protein-coupled receptor-dependent cytoskeletal reorganization [11]. GRK2 regulates cell migration during wound recovery in epithelial cell monolayers, at least partly by phosphorylating radixin [12]. Nick interacting kinase (NIK)-induced phosphorylation of ezrin on Thr567 is necessary for lamellipodium extension induced by growth factors [13]. Lymphocyte-oriented-kinase (LOK) is a major ERM kinase in resting lymphocytes, and phosphorylation of ezrin regulates the cytoskeletal organization of lymphocytes [14]. Protein kinase C (PKC) phosphorylates ezrin to regulate osteosarcoma cell migration [15]. PKC-alpha has been shown to prefer ezrin as its target for phosphorylation [16], while PKC-theta prefers to phosphorylate moesin on Thr558 [17]. However, phosphorylation of ezrin by PKC-iota is essential for its normal distribution, and may be involved in the differentiation of intestinal epithelial cells [18].

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Initial prescriptions of sedatives among older stroke survivors may include too many pills

 Well, your competent? doctor has had a lot to analyze on this already. If your doctor isn't very familiar with this research, YOU DON'T HAVE A FUNCTIONING STROKE DOCTOR!

Benzodiazepines Associated With Increased Risk of Alzheimer’s Disease August 2018

But what about this research?

Benzodiazepines May Have Protective Effects Against Alzheimer Disease March 1998

The latest here:

Initial prescriptions of sedatives among older stroke survivors may include too many pills

             Initial prescriptions of benzodiazepines, a class of drugs used to treat anxiety and sleep problems after a stroke may include too many pills for adults ages 65 or older, finds new study in the Stroke journal

Research Highlights

• Within 90 days after having an ischemic (clot-caused) stroke, about 5% of stroke survivors ages 65 and older were prescribed  (depressants that relieve anxiety, muscle spasms, produce sedation and reduce seizures) for the first time.
• More than half of the new prescriptions of benzodiazepines were written for a supply of 15 to 30 days, rather than the smaller number of pills for short-term, as-needed use.  
• The study also found that women were more likely than men to receive an initial prescription for benzodiazepines after having a stroke.

Embargoed until 4 a.m. CT/5 a.m. ET, Thursday, Oct. 17, 2024

DALLAS, Oct. 17, 2024 — Although there has been a slight downward trend in the prescription of benzodiazepines (depressants that relieve anxiety, muscle spasms, produce sedation and reduce seizures) among older adults over the last decade, the rate of first-time prescriptions for these medications after an ischemic (clot-caused) stroke is still sizable, according to research published today in Stroke, the peer-reviewed scientific journal of the American Stroke Association, a division of the American Heart Association.

After a stroke, benzodiazepines may be used to calm anxiety and improve sleep. However, when prescribed to older adults, these medications may increase the risk of falls and broken bones, as well as memory problems, confusion and other harmful effects. The U.S. Drug Enforcement Agency lists benzodiazepines as a schedule IV-controlled substance and have the potential for abuse, addiction, withdrawal and illegal distribution.

Researchers reviewed data from Medicare claims in the U.S. and analyzed 10 years of first-time prescriptions for benzodiazepines among more than 120,000 people, ages 65 and older, who were hospitalized for ischemic stroke. The rate of benzodiazepine prescriptions during the first three months after stroke were examined, and data were adjusted for race, sex and ethnicity. Then year-to-year prescription patterns were reviewed to identify the number of potentially excessive new benzodiazepine prescriptions given to stroke survivors.

“We reviewed stroke survivors at 90 days after a stroke because that window of time is critical for rehabilitation of motor, speech and cognitive function, as well as mental health. It’s often a very difficult time for patients who experience loss of mobility and independence. Benzodiazepines may inhibit recovery and rehabilitation,” said study co-author Julianne Brooks, M.P.H., a data analytics manager at the Center for Value-based Healthcare and Sciences at Massachusetts General Brigham in Boston. “For this older age group, guidelines recommend that benzodiazepine prescriptions should be avoided if possible. However, there may be cases where benzodiazepines are prescribed to be used as needed. For example, to treat breakthrough anxiety, a provider may prescribe a few pills and counsel the patient that the medication should only be used as needed. The increased risks of dependence, falls and other harmful effects should be discussed with the patient.”

The study found:

• Within 90 days of stroke, 6,127 (4.9%) people were started on a benzodiazepine for the first time.
• Lorazepam (40%) and alprazolam (33%) were the most-prescribed benzodiazepine medications.
• Three-quarters of the first-time benzodiazepine prescriptions were for a supply of over seven days, and more than half of the prescriptions were for a supply between 15 to 30 days.
• Prescription rates were higher among women (5.5%) than men (3.8%).
• Prescription fill rates were also higher in Hispanic adults (5.8%), though this group was limited by the small number of participants - 1.9% of the overall sample.
• Overall, prescription rates were highest in the Southeast (5.1%) and lowest in the Midwest (4%) of the U.S. “The Southeast region is the stroke belt with a higher rate of strokes, so that could explain some differences in care in that region,” Brooks said.
• There was an overall modest nationwide decline of initial prescriptions from 2013 to 2021 of 1.6%.

“We found a pattern of potential oversupply with these initial benzodiazepine prescriptions, which would be enough for patients to become long-term users or possibly addicted. The benzodiazepine prescriptions given under these circumstances may lead to dependence,” Brooks said. “Increased awareness and improved recommendations about the risks of these medications for older stroke survivors are needed. 

“Although the overall prescription rate decreased slightly over 10 years, this prescription pattern is still a problem. It’s concerning because older adults are vulnerable to overprescribing and adverse outcomes. We know from previous studies that vulnerable and marginalized populations experience worse outcomes after stroke, so we want to understand the factors that may play a role so we can provide better care,” Brooks said.

The 2019 American Geriatrics Society Beers Criteria maintains a list of medications that health care professionals can reference to safely prescribe medications for adults older than 65. Beers criteria recommends avoiding benzodiazepines in all older adults due to the risk of cognitive impairment, delirium, falls, fractures and motor vehicle crashes.

“Other guidelines also suggest behavioral interventions such as cognitive behavior therapy for insomnia, antidepressant medications for anxiety disorders and trying non-pharmaceutical interventions first,” Brooks said.

Researchers said more studies are needed to understand if there is a safe level for prescribing benzodiazepines that may be most appropriate for older adults. The main limitation was that this study used a large, national dataset that did not include information about why benzodiazepines were prescribed.

According to the American Heart Association’s Heart Disease and Stroke Statistics 2024 Update, stroke is a leading cause of serious long-term disability in the U.S. and accounted for approximately 1 of every 21 deaths in the United States in 2021.

Study details, background and design:

• The analysis included the records of 126,050 adults from U.S. Medicare claims for all adults ages 65 and older discharged from the hospital for ischemic stroke between 2013 and 2021.
• Their average age was 78; 54% were self-identified as female, and 82% were self-identified as white adults.
• The analysis examined new prescriptions of benzodiazepines within 90 days of discharge after ischemic stroke. The study only included people who had no previous benzodiazepine prescriptions.

Co-authors, disclosures and funding sources are listed in the manuscript. 

Studies published in the American Heart Association’s scientific journals are peer-reviewed. The statements and conclusions in each manuscript are solely those of the study authors and do not necessarily reflect the Association’s policy or position. The Association makes no representation or guarantee as to their accuracy or reliability. The Association receives funding primarily from individuals; foundations and corporations (including pharmaceutical, device manufacturers and other companies) also make donations and fund specific Association programs and events. The Association has strict policies to prevent these relationships from influencing the science content. Revenues from pharmaceutical and biotech companies, device manufacturers and health insurance providers and the Association’s overall financial information are available here. 

U of Idaho robotics help stroke survivors regain mobility

 I can't see that much help here since nothing is being done recover the fingers. I'd wait until I see the mobile versions since this would have to get you completely recovered while still in the hospital.

U of I robotics help stroke survivors regain mobility

Repetitive peripheral magnetic stimulation alone or in combination with repetitive transcranial magnetic stimulation in poststroke rehabilitation: a systematic review and meta-analysis

 Instead of doing lazy crapola review research like this, WHY THE FUCK AREN'T YOU PROVIDING RESEARCH THAT GETS SURVIVORS RECOVERED? Are your mentors and senior researchers that fucking incompetent? 

Send me hate mail on this: oc1dean@gmail.com. I'll print your complete statement with your name and my response in my blog. Or are you afraid to engage with my stroke-addled mind? I would like to know why you aren't creating research that gets survivors recovered!

You'll want 100% recovery when you become the 1 in 4 per WHO that has a stroke!). I'd suggest you start working on that now!

Repetitive peripheral magnetic stimulation alone or in combination with repetitive transcranial magnetic stimulation in poststroke rehabilitation: a systematic review and meta-analysis

• Yong Wang,
• Kenneth N. K. Fong,
• Youxin Sui,
• Zhongfei Bai &
• Jack Jiaqi Zhang 

Journal of NeuroEngineering and Rehabilitation volume 21, Article number: 181 (2024) Cite this article

• Metrics details

Abstract

Objective

This study aimed to comprehensively review the effects of repetitive peripheral magnetic stimulation (rPMS) alone or in combination with repetitive transcranial magnetic stimulation (rTMS) on improving upper limb motor functions and activities of daily living (ADL) in patients with stroke, and to explore possible efficacy-related modulators.

Methods

A literature search from 1st January 2004 to 1st June 2024 was performed to identified studies that investigated the effects of rPMS on upper limb motor functions and ADL in poststroke patients.

Results

Seventeen studies were included. Compared with the control, both rPMS alone or rPMS in combination with rTMS significantly improved upper limb motor function (rPMS: Hedge’s g = 0.703, p = 0.015; rPMS + rTMS: Hedge’s g = 0.892, p < 0.001) and ADL (rPMS: Hedge’s g = 0.923, p = 0.013; rPMS + rTMS: Hedge’s g = 0.923, p < 0.001). However, rPMS combined with rTMS was not superior to rTMS alone on improving poststroke upper limb motor function and ADL (Hedge’s g = 0.273, p = 0.123). Meta-regression revealed that the total pulses (p = 0.003) and the number of pulses per session of rPMS (p < 0.001) correlated with the effect sizes of ADL.

Conclusions

Using rPMS alone or in combination with rTMS appears to effectively improve upper extremity functional recovery and activity independence in patients after stroke. However, a simple combination of these two interventions may not produce additive benefits than the use of rTMS alone. Optimization of rPMS protocols, such as applying appropriate dosage, may lead to a more favourable recovery outcome in poststroke rehabilitation.

Introduction

Repetitive peripheral magnetic stimulation (rPMS) is a non-invasive therapeutic approach for facilitating motor recovery following neurological diseases, which was first proposed for the purpose of neurological rehabilitation in 1996 [1]. The rPMS technique employs focused magnetic pulses over various peripheral targets (e.g., muscles, nerves, or spinal roots) [2], and this technique induces repetitive contraction-relaxation cycles by depolarizing neurons [3] and then provides proprioceptive inputs to afferent fibers [4,5,6,7], therefore modulating sensorimotor plasticity. In the literature, rPMS is considered a unique, promising neuromodulation technique due to its advantage of providing more deeply penetrating, focused, painless stimulation than conventional electrical stimulation provides [5, 8, 9].

In 2023, rPMS was delivered using a transcranial magnetic stimulator, which was originally used for repetitive transcranial magnetic stimulation (rTMS), and has been approved by the US Food and Drug Administration for relieving chronic pain [10]. In poststroke rehabilitation, rPMS is different from rTMS in the neural mechanism - rTMS has been extensively used to facilitate motor recovery by modulating cortical plasticity in a top-down approach [11] whereas rPMS is adopting a bottom-up approach through recruitment of proprioceptive afferents thus up-regulate the excitability of the sensorimotor areas via the ascending pathway [2, 6]. Therefore, combining central and peripheral magnetic stimulation may produce a synergistic effect on the facilitation of motor recovery after stroke [12].

The effects of rPMS for motor function of the hemiplegic upper extremity or ADL after stroke have been reviewed in previous systematic reviews, which generally have reported positive effects of rPMS [2, 8, 13,14,15,16,17,18]. However, these reviews are not free from methodological limitations. Firstly, a few reviews did not perform meta-analysis to quantitively evaluate the treatment effects [2, 14, 18]. Secondly, in the previous meta-analytic reviews, no detailed subgroup analysis or meta-regression was performed to identify the influence of different stimulation protocols, patient demographics, or patients’ clinical profiles on the treatment effect sizes [8, 13, 15, 16]. Thirdly, some reviews covered a wide range of neurological disease conditions, so the specific effect of rPMS in stroke rehabilitation was still not conclusive [2, 17]. Lastly, these reviews did not systematically investigate the effect of rPMS alone or in combination with rTMS to elaborate the possible synergistic effect of the combined interventions [2, 8, 13,14,15,16,17,18].

Therefore, a comprehensive understanding of clinical effectiveness as well as neural mechanisms underlying the therapeutic benefits of using rPMS alone or in combination with rTMS in poststroke rehabilitation is needed. Here, our review aimed to: (1) investigate the effects of these two interventional methods (using rPMS alone or in combination with rTMS) on upper limb motor function and ADL in poststroke patients, using meta-analysis; (2) identify any significant relationship between various rPMS parameters, patient demographics, clinical characteristics, and effect sizes using subgroup analyses and meta-regression; and (3) clarify the mechanisms underlying the therapeutic effects of rPMS by qualitatively assessing rPMS studies using neuroimaging and/or neurophysiological outcomes.