Age is characterized by chronic inflammation, leading to synaptic dysfunction and dementia because the clearance of protein waste is reduced. The clearance of proteins depends partly on the permeation of the blood–brain barrier (BBB) or on the exchange of water and soluble contents between the cerebrospinal fluid and the interstitial fluid (ISF). A wealth of evidence indicates that physical exercise improves memory and cognition in neurodegenerative diseases during aging, such as Alzheimer's disease, but the influence of physical training on glymphatic clearance, BBB permeability, and neuroinflammation remains unclear. In this study, glymphatic clearance and BBB permeability were evaluated in aged mice using in vivo two-photon imaging. The mice performed voluntary wheel running exercise and their water-maze cognition was assessed; the expression of the astrocytic water channel aquaporin 4 (AQP4), astrocyte and microglial activation, and the accumulation of amyloid beta (Aβ) were evaluated with immunofluorescence or an enzyme-linked immunosorbent assay; synaptic function was investigated with Thy1–green fluorescent protein transgenic mice and immunofluorescent staining. Voluntary wheel running significantly improved water-maze cognition in the aged mice, accelerated the efficiency of glymphatic clearance, but which did not affect BBB permeability. The numbers of activated astrocytes and microglia decreased, AQP4 expression increased, and the distribution of astrocytic AQP4 was rearranged. Aβ accumulation decreased, whereas dendrites, dendritic spines, and postsynaptic density protein increased. Our study suggests that voluntary wheel running accelerated glymphatic clearance but not BBB permeation, improved astrocytic AQP4 expression and polarization, attenuated the accumulation of amyloid plaques and neuroinflammation, and ultimately protected mice against synaptic dysfunction and a decline in spatial cognition. These data suggest possible mechanisms for exercise-induced neuroprotection in the aging brain.

Dual task (DT) is a commonly used paradigm indicative of executive functions. Brain activities during DT walking is usually measured by portable functional near infrared spectroscopy (fNIRS). Previous studies focused on cortical activation in prefrontal cortex and overlooked other brain regions such as sensorimotor cortices. This study is aimed at investigating the modulations of cortical activation and brain network efficiency in multiple brain regions from single to dual tasks with different complexities and their relationships with DT performance. Forty-two healthy adults [12 males; mean age: 27.7 (SD=6.5) years] participated in this study. Participants performed behavioral tasks with portable fNIRS simultaneous recording. There were three parts of behavioral tasks: cognitive tasks while standing (serial subtraction of 3's and 7's), walking alone and DT (walk while subtraction, including serial subtraction of 3's and 7's). Cognitive cost, walking cost and cost sum (i.e., sum of cognitive and walking costs) were calculated for DT. Cortical activation, local and global network efficiency were calculated for each task. The cognitive cost was greater and the walking cost was less during DT with subtraction 3's compared with 7's (P's = 0.032 and 0.019, respectively). Cortical activation and network efficiency were differentially modulated among single and dual tasks (P's < 0.05). Prefrontal activation during DT was positively correlated with DT costs, while network efficiency was negatively correlated with DT costs (P's < 0.05). Our results revealed prefrontal over-activation and reduced network efficiency in individuals with poor DT performance. Our findings suggest that reduced network efficiency could be a possible mechanism contributing to poor DT performance, which is accompanied by compensatory prefrontal over-activation.

Objective:Intermittent theta burst stimulation (iTBS) is a special form of repetitive transcranial magnetic stimulation (rTMS), which effectively increases cortical excitability and has been widely used as a neural modulation approach in stroke rehabilitation. As effects of iTBS are typically investigated by motor evoked potentials, how iTBS influences functional brain network following stroke remains unclear. Resting-state electroencephalography (EEG) has been suggested to be a sensitive measure for evaluating effects of rTMS on brain functional activity and network. Here, we used resting-state EEG to investigate the effects of iTBS on functional brain network in stroke survivors.Methods:We studied thirty stroke survivors (age: 63.1 ± 12.1 years; chronicity: 4.0 ± 3.8 months; UE FMA: 26.6 ± 19.4/66) with upper limb motor dysfunction. Stroke survivors were randomly divided into two groups receiving either Active or Sham iTBS over the ipsilesional primary motor cortex. Resting-state EEG was recorded at baseline and immediately after iTBS to assess the effects of iTBS on functional brain network.Results:Delta and theta bands interhemispheric functional connectivity were significantly increased after Active iTBS (P= 0.038 and 0.011, respectively), but were not significantly changed after Sham iTBS (P= 0.327 and 0.342, respectively). Delta and beta bands global efficiency were also significantly increased after Active iTBS (P= 0.013 and 0.0003, respectively), but not after Sham iTBS (P= 0.586 and 0.954, respectively).Conclusion:This is the first study that used EEG to investigate the acute neuroplastic changes after iTBS following stroke. Our findings for the first time provide evidence that iTBS modulates brain network functioning in stroke survivors. Acute increase in interhemispheric functional connectivity and global efficiency after iTBS suggest that iTBS has the potential to normalize brain network functioning following stroke, which can be utilized in stroke rehabilitation.

Background: Repetitive transcranial magnetic stimulation (rTMS) is a promising intervention for stroke rehabilitation. Several studies have demonstrated the effectiveness of rTMS in restoring motor function. This meta-analysis aimed to summarize the current evidence of the effect of rTMS in improving upper limb function and fine motor recovery in stroke patients.Methods: Three online databases (Web of Science, PubMed, and Embase) were searched for relevant randomized controlled trials. A total of 45 studies (combined n = 2064) were included. Random effects model was used for meta-analysis and effect size was reported as standardized mean difference (SMD).Results: rTMS was effective in improving fine motor function in stroke patients (SMD, 0.38; 95% CI 0.19–0.58; P = 0). On subgroup analyses, for post-stroke functional improvement of the upper extremity, bilateral hemisphere stimulation was more effective than unilateral stimulation during the acute phase of stroke, and a regimen of 20 rTMS sessions produced greater improvement than <20 sessions. In the subacute phase of stroke, affected hemispheric stimulation with a 40-session rTMS regimen was superior to unaffected hemispheric stimulation or bilateral hemispheric stimulation with 10 rTMS sessions. For the rTMS stimulation method, both TBS and rTMS were found to be significantly more effective in the acute phase of stroke, but TBS was more effective than rTMS. However, rTMS was found to be more effective than TBS stimulation in patients in the subacute and chronic phases of stroke. rTMS significantly improved upper limb and fine function in the short term (0–1-month post-intervention) and medium term (2–5 months), but not for upper limb function in the long term (6 months+). The results should be interpreted with caution due to significant heterogeneity.Conclusions: This updated meta-analysis provides robust evidence of the efficacy of rTMS treatment in improving upper extremity and fine function during various phases of stroke.Systematic Review Registration: https://inplasy.com/inplasy-2022-5-0121/, identifier: INPLASY202250121.

Repetitive transcranial magnetic stimulation (rTMS) technology, which is amongst the most used non-invasive brain stimulation techniques currently available, has developed rapidly from 2009 to 2018. However, reports on the trends of rTMS using bibliometric analysis are rare. The goal of the present bibliometric analysis is to analyze and visualize the trends of rTMS, including general (publication patterns) and emerging trends (research frontiers), over the last 10 years by using the visual analytic tool CiteSpace V. Publications related to rTMS from 2009 to 2018 were retrieved from the Web of Science (WoS) database, including 2,986 peer-reviewed articles/reviews. Active authors, journals, institutions, and countries were identified by WoS and visualized by CiteSpace V, which could also detect burst changes to identify emerging trends. GraphPad Prism 8 was used to analyze the time trend of annual publication outputs. The USA ranked first in this field. Pascual-Leone A (author A), Fitzgerald PB (author B), George MS (author C), Lefaucheur JP (author D), and Fregni F (author E) made great contributions to this field of study. The most prolific institution to publish rTMS-related publications in the last decade was the University of Toronto. The journal Brain Stimulation published most papers. Lefaucheur et al.'s paper in 2014, and the keyword “sham controlled trial” showed the strongest citation bursts by the end of 2018, which indicates increased attention to the underlying work, thereby indicating the research frontiers. This study reveals the publication patterns and emerging trends of rTMS based on the records published from 2009 to 2018. The insights obtained have reference values for the future research and application of rTMS.