Effects of Priming Intermittent Theta Burst Stimulation With High-Definition tDCS on Upper Limb Function in Hemiparetic Patients With Stroke: A Randomized Controlled Study.

BACKGROUND: Preconditioning with cathodal high-definition transcranial direct current stimulation (HD-tDCS) can potentiate cortical plasticity induced by intermittent theta burst stimulation (iTBS) and enhance the after-effects of iTBS in healthy people. However, it is unclear whether this multi-modal protocol can enhance upper limb function in patients with stroke. OBJECTIVE: The aim of this study was to investigate whether priming iTBS with cathodal HD-tDCS over the ipsilesional M1 can augment upper limb motor recovery in poststroke patients. METHODS: A total of 66 patients with subacute stroke were randomly allocated into 3 groups. Group 1 received priming iTBS with HD-tDCS (referred to as the tDCS + iTBS group), Group 2 received non-priming iTBS (the iTBS group), and Group 3 received sham stimulation applied to the ipsilesional M1. One session was performed per day, 5 days per week, for 3 consecutive weeks. In Group 1, iTBS was preceded by a 20-minute session of cathodal HD-tDCS at a 10-minute interval. The primary outcome measure was the Fugl-Meyer Assessment-Upper Extremity (FMA-UE) score. Moreover, the secondary outcome measures for muscle strength and spasticity were the Motricity Index-Upper Extremity (MI-UE) and the Modified Ashworth Scale Upper-Extremity (MAS-UE), respectively, and the Hong Kong Version of the Functional Test for the Hemiplegic Upper Extremity (FTHUE-HK) and the Modified Barthel Index (MBI) for activity and participation. RESULTS: Significant differences were detected in the changes in FMA-UE, MI-UE, and MBI scores between the 3 groups from baseline to post-intervention (χ2FMA-UE = 10.856, P = .004; χ2MI-UE = 6.783, P = .034; χ2MBI = 9.608, P = .008). Post hoc comparisons revealed that the priming iTBS group demonstrated substantial improvements in FMA-UE (P = .004), MI-UE (P = .028), and MBI (P = 0.006) compared with those in the sham group. However, no significant difference was observed between the iTBS group and the sham group. Moreover, no significant differences were found in the changes in MAS-UE or FTHUE-HK between the groups. CONCLUSIONS: Priming iTBS with HD-tDCS over the ipsilesional M1 cortex had beneficial effects on augmenting upper limb motor recovery and enhancing daily participation among subacute stroke patients.

Combined effects of transcranial direct current stimulation and aerobic exercise on inhibitory control function in healthy young adults: An event-related potential study.

Transcranial direct current stimulation (tDCS) and aerobic exercise (AE) have been demonstrated to enhance inhibitory control function in healthy individuals separately. However, the potential benefits of combining these two interventions have yet to be fully explored. In this study, we aimed to use multiple event-related potential (ERP) components (P200, N200, and N450) to investigate the combined effects of tDCS and AE on the improvement of inhibitory control ability in healthy young adults. We evaluated the influence of this combined intervention on cognitive tasks involving inhibitory control function and basic information processing by performing the Stroop Word Color task. Our results showed that compared to the application of tDCS or AE alone, the combined intervention of tDCS and AE had a greater effect on improving inhibitory control function in healthy young adults. The amplitude of P200, N200, and N450 ERP components also changed more significantly during the Stroop Word Color task. We concluded that the mechanism of tDCS combined with AE in improving inhibitory control ability may involve synergistic effects on brain structures at different levels, such as regulating interactions at the reticular activating system level and activating corresponding brain regions at the medial frontal lobe and frontal lobe levels.

Bidirectional causal association between ischemic stroke and five mental disorders.

OBJECTIVE: To explore the bidirectional causal association between ischemic stroke and five mental disorders from a genetic perspective using two-sample Mendelian randomization (TSMR). METHODS: Single-nucleotide polymorphisms (SNPs) associated with ischemic stroke were obtained from the genome-wide association study (GWAS) database, and those closely related to the exposure phenotype and satisfying the three core assumptions of Mendelian randomization were selected as instrumental variables (IVs). The main TSMR analysis was conducted using the inverse variance-weighted (IVW) method, and the robustness of the results was assessed using the weighted median, weighted mode, and MR Egger methods. Heterogeneity test, pleiotropy test, and sensitivity analysis were also conducted to further ensure the accuracy and stability of the research results. RESULTS: This study found a positive correlation between ischemic stroke and depression [IVW method (FEM): OR = 1.002, 95%CI: 1.000-1.003, P = 0.023<0.05], but no significant causal association with schizophrenia, bipolar disorder, insomnia, or anxiety (P > 0.05). Reverse TSMR analysis showed no causal association between depression, schizophrenia, bipolar disorder, insomnia, anxiety, and ischemic stroke (P > 0.05). CONCLUSION: This study used TSMR to demonstrate from a genetic perspective that there is a positive correlation between ischemic stroke and depression, which increases the risk of depression. Proactive intervention for ischemic stroke might reduce the risk of depression.

Synergistic effects of aerobic exercise and transcranial direct current stimulation on executive function and biomarkers in healthy young adults.

OBJECTIVE: This research explored the combined effects of transcranial direct current stimulation (tDCS) and aerobic exercise (AE) on executive function and specific serum biomarkers in healthy adults. METHODS: Sixty healthy young adults were randomly assigned into tDCS+AE, tDCS only, or AE only groups. Interventions were carried out for 20 days. Executive functions were evaluated using tasks such as the 2,3-back task, the spatial working memory task, the Stroop test, T test, and hexagonal obstacle jump task. Serum biomarkers, including brain-derived neurotrophic factor (BDNF), malondialdehyde (MDA), superoxide dismutase (SOD), glutamate, glutathione peroxidase 4 (GPX4) and iron ion, were analyzed pre- and post-intervention. RESULTS: The tDCS+AE group showed superior enhancements in executive function, evidenced by improved accuracy rates in 2,3-back tasks, better performance in the staircase task, and reduced reaction times in the incongruent reaction time of the Stroop task compared to other groups. Importantly, we found substantial changes in serum biomarkers: increased levels of BDNF and SOD, and decreased levels of MDA and glutamate in the tDCS+AE group. These changes were significantly different when compared with the tDCS and AE only groups. Notably, these alterations in serum biomarkers were correlated with improvements in executive function tasks, thus offering a potential physiological basis for the cognitive improvements witnessed. CONCLUSION: The combined tDCS and AE intervention effectively improved executive function in healthy young adults, with the improvements linked to changes in key serum biomarkers. The results emphasize the potential of combined tDCS and AE interventions in engaging multiple physiological pathways to enhance executive function.

Incidence and risk factors of post-stroke cognitive impairment in convalescent elderly patients with first-episode acute ischemic stroke.

A total of 350 first-time AIS elderly patients (aged ≥60 years) were collected and analyzed. Multivariate Logistic regression analysis showed that the lesion site, frontal temporal, cerebral white matter degeneration, age ≥ 75 years, BMI ≥ 28, onset in autumn/winter, hospitalization expenses > 20,000 yuan/month, high DBPV, high NIHSS score, and high HAMD score were risk factors for PSCI. Higher education level was a protective factor. In conclusion, the incidence of PSCI in elderly AIS patients was relatively high and related to the several factors, which indicated that more attention should be paid for such patients to prevent PSCI.

Insight into the potential role of ferroptosis in neurodegenerative diseases.

Ferroptosis is a newly discovered way of programmed cell death, mainly caused by the accumulation of iron-dependent lipid peroxides in cells, which is morphologically, biochemically and genetically different from the previously reported apoptosis, necrosis and autophagy. Studies have found that ferroptosis plays a key role in the occurrence and development of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and vascular dementia, which suggest that ferroptosis may be involved in regulating the progression of neurodegenerative diseases. At present, on the underlying mechanism of ferroptosis in neurodegenerative diseases is still unclear, and relevant research is urgently needed to clarify the regulatory mechanism and provide the possibility for the development of agents targeting ferroptosis. This review focused on the regulatory mechanism of ferroptosis and its various effects in neurodegenerative diseases, in order to provide reference for the research on ferroptosis in neurodegenerative diseases.

Cerebellar Continuous Theta Burst Stimulation for Aphasia Rehabilitation: Study Protocol for a Randomized Controlled Trial.

Background: Language recovery is limited in moderate to severe post-stroke aphasia patients. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising tool in improving language dysfunctions caused by post-stroke aphasia, but the treatment outcome is as yet mixed. Considerable evidence has demonstrated the essential involvement of the cerebellum in a variety of language functions, suggesting that it may be a potential stimulation target of TMS for the treatment of post-stroke aphasia. Theta burst stimulation (TBS) is a specific pattern of rTMS with shorter stimulation times and better therapeutic effects. The effect of continuous TBS (cTBS) on the cerebellum in patients with aphasia with chronic stroke needs further exploration. Methods: In this randomized, sham-controlled clinical trial, patients (n = 40) with chronic post-stroke aphasia received 10 sessions of real cTBS (n = 20) or sham cTBS (n = 20) over the right cerebellar Crus I+ a 30-min speech-language therapy. The Western Aphasia Battery (WAB) serves as the primary measure of the treatment outcome. The secondary outcome measures include the Boston Diagnostic Aphasia Examination, Boston Naming Test and speech acoustic parameters. Resting-state fMRI data were also obtained to examine treatment-induced changes in functional connectivity of the cerebro-cerebellar network. These outcome measures are assessed before, immediately after, and 12 weeks after cerebellar cTBS intervention. Discussion: This protocol holds promise that cerebellar cTBS is a potential strategy to improve language functions in chronic post-stroke aphasia. The resting-state fMRI may explore the neural mechanism underlying the aphasia rehabilitation with cerebellar cTBS.

Effects of the Intermittent Theta Burst Stimulation of the Cerebellar Vermis on Balance Recovery After Stroke: A Study Protocol for a Randomized Controlled Trial.

Background: The recovery of balance function is a critical segment in the rehabilitation treatment of stroke. The cerebellum is considered as the key structure involved in balance and motor control. The cerebellar vermis plays an important role in integrating vision, proprioception, and sensory skin input and may be a candidate stimulation target for regulating the motor network related with balance. However, evidence that the intermittent theta burst stimulation (iTBS) of cerebellar vermis can promote the recovery of balance function after stroke remains insufficient. Therefore, this study aims to explore the efficacy of the cerebellar vermis iTBS for the treatment of balance function in patients with stroke. Methods and Analysis: Forty patients with stroke will be recruited in this prospective, randomized, sham-controlled trial. Participants will be randomized in a 1:1 ratio to receive either 15 sessions of cerebellar vermis iTBS (600 pulses) or sham stimulation. Additionally, a routine rehabilitation therapy follows the intervention. The primary outcome is the Berg Balance Scale, and the secondary outcomes are the Fugl-Meyer assessment of the lower extremity and modified Barthel index. The above outcomes will be assessed before intervention and at the end of each week. Pre- and post-iTBS resting-state functional magnetic resonance imaging (rs-fMRI) will be acquired, and the regional homogeneity, fractional amplitude of low-frequency fluctuation and functional connectivity will be calculated and analyzed. Discussion: This protocol holds promise as a potential method to improve balance function in patients with stroke. If the outcomes of patients improve after the intervention, the study will provide new insights into improving balance function. Ethics and Dissemination: This study has been approved by the Medical Research Ethics Committee of Wuxi Mental Health Center (Wuxi Tongren Rehabilitation Hospital). Results will be disseminated through (open-access) peer-reviewed publications, networks of scientists, professionals, and the public and presented at conferences. Clinical Trial Registration Number: www.chictr.org.cn, identifier ChiCTR2100052590.

Continuous theta burst stimulation-induced suppression of the right fronto-thalamic-cerebellar circuit accompanies improvement in language performance in poststroke aphasia: A resting-state fMRI study.

Background: Continuous theta burst stimulation (cTBS) is a specific paradigm of repetitive transcranial magnetic stimulation (rTMS) with an inhibitory effect on cortical excitability for up to 60 min after less than 1 min of stimulation. The right posterior superior temporal gyrus (pSTG), homotopic to Wernicke's area in the left hemisphere, may be a potential stimulation target based on its critical role in semantic processing. The objective of this study was to explore whether cTBS over the right pSTG can promote language improvements in aphasic patients and the underlying mechanism. Methods: A total of 34 subjects with aphasia were randomly assigned to undergo 15 sessions of either 40-s inhibitory cTBS over the right pSTG (the cTBS group) or sham stimulation (the sham group), followed by 30 min of speech and language therapy. Subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI), and the aphasia quotient (AQ) of the Chinese version of the Western Aphasia Battery (WAB) was calculated before and after the intervention. This randomized controlled trial was registered in the Chinese Clinical Trial Registry (No. ChiCTR210052962). Results: After treatment, the language performance of the cTBS group was higher than that of the sham group in terms of the WAB-AQ score (p = 0.010) and the WAB scores for auditory comprehension (p = 0.022) and repetition (p = 0.035). The fractional amplitude of low-frequency fluctuations (fALFF) was significantly decreased in the pars triangularis of the inferior frontal gyrus (IFG), right middle frontal gyrus, right thalamus, and left cerebellar crus I. Clusters in the left orbitofrontal cortex exhibited increased fALFF. The change in WAB comprehension scores were significantly correlated with the change in the fALFF of the right IFG pars triangularis in both groups. Greatly increased functional connectivity was observed between the right pars triangularis and left paracingulate gyrus and between the right pSTG and right angular gyrus and the posterior cingulate gyrus with pre-and post-treatment between the two groups. Conclusion: Our findings indicate that cTBS of the right pSTG may improve language production by suppressing intrinsic activity of the right fronto-thalamic-cerebellar circuit and enhancing the involvement of the right temporoparietal region.

Exploring the functional connectivity characteristics of brain networks in post-stroke patients with global aphasia: a healthy control based resting-state fMRI study.

BACKGROUND: In this study, resting-state functional magnetic resonance imaging (rs-fMRI) was used to investigate the characteristics of functional connectivity of brain networks in patients with post-stroke global aphasia (PGA). METHODS: PGA patients hospitalized in Wuxi Tongren Rehabilitation Hospital during their subacute stage were selected as a case group, and healthy volunteers with matching age, sex, and education level were selected as healthy controls (HCs). rs-fMRI scans were performed to compare the differences of functional connectivity in resting-state networks (RSNs) and in the whole brain between the two groups. RESULTS: A total of 11 patients with PGA and 11 HCs were included in this study. PGA patients showed decreased inter-hemispheric connectivity of homologs within the sensorimotor network (SMN), salience network, and language network. In the analysis of the whole brain functional connections, PGA patients exhibited both inter-hemispheric and intra-hemispheric hypoconnectivity when compared with HCs. However, they exhibited some stronger connections than HCs between the language network and cerebellar network, which may indicate compensatory mechanisms. CONCLUSIONS: Using rs-fMRI to research differences in the functional connectivity of brain networks in post-stroke global aphasia will help us further understand it's neurological mechanism and provide an important basis for the accurate selection of therapeutic targets in the future to promote better recovery of language function.

Effects of the introduction of objective criteria for referral and discharge in physical therapy for ischemic stroke in China: a randomized controlled trial.

OBJECTIVE: To examine the effectiveness of a set of rules for referral and therapy input in a three-tiered physiotherapy program on activities of daily living (ADL), motor function, and quality of life of stroke survivors. DESIGN: Randomized controlled study. SETTING: Rehabilitation departments of 11 teaching hospitals. SUBJECTS: A total of 285 participants with stroke. OUTCOME MEASURES: Primary outcome was ADL independence measured with the Modified Barthel Index (MBI) at weeks 3, 6, 9, 13, and 17. Secondary outcomes were motor function and quality of life measured with Fugel-Meyer Assessment (FMA) and Stroke-Specific Quality-of-Life (SSQOL) scale. INTERVENTION: Two complementary sets of rules governing rehabilitation delivery were introduced: a set of criteria that determined when someone ought to move from tier 1 onto tier 2, and from tier 2 onto tier 3, and a second set of rules that determined the amount and type of physiotherapy input given in each tier. Control group participants received conventional rehabilitation without any specified guidelines. RESULTS: With a difference of 3.97 (95% confidence interval (CI): 1.59-6.36), MBI increased stronger in the study group than in controls between baseline and week 3 (P = 0.001). This difference could be sustained until study end-point. No significant differences were found for FMA. Differences in increase of SSQOL were higher in the intervention than control at week 9 (P < 0.05). CONCLUSION: Introduction of a set of rules for referral and therapy input at different stages of rehabilitation partially improved patients' ADL and quality of life, but did not improve motor function.

The Effect of rTMS over the Different Targets on Language Recovery in Stroke Patients with Global Aphasia: A Randomized Sham-Controlled Study.

OBJECTIVE: To evaluate and compare the effects of repetitive transcranial magnetic stimulation (rTMS) over the right pars triangularis of the posterior inferior frontal gyrus (pIFG) and the right posterior superior temporal gyrus (pSMG) in global aphasia following subacute stroke. METHODS: Fifty-four patients with subacute poststroke global aphasia were randomized to 15-day protocols of 20-minute inhibitory 1 Hz rTMS over either the right triangular part of the pIFG (the rTMS-b group) or the right pSTG (the rTMS-w group) or to sham stimulation, followed by 30 minutes of speech and language therapy. Language outcomes were assessed by aphasia quotient (AQ) scores obtained from the Chinese version of the Western Aphasia Battery (WAB) at baseline and immediately after 3 weeks (15 days) of experimental treatment. RESULTS: Forty-five patients completed the entire study. The primary outcome measures include the changes in WAB-AQ score, spontaneous speech, auditory comprehension, and repetition. These measures indicated significant main effect between the baseline of the rTMS-w, rTMS-b, and sham groups and immediately after stimulation (P<0.05). Compared with the sham group, the increases were significant for auditory comprehension, repetition, and AQ in the rTMS-w group (P<0.05), whereas the changes in repetition, spontaneous speech, and AQ tended to be higher in the rTMS-b group (P<0.05). CONCLUSIONS: Inhibitory rTMS targeting the right pIFG and pSTG can be an effective treatment for subacute stroke patients with global aphasia. The effect of rTMS may depend on the stimulation site. Low-frequency rTMS inhibited the right pSTG and significantly improved language recovery in terms of auditory comprehension and repetition, whereas LF-rTMS inhibited the right pIFG, leading to apparent changes in spontaneous speech and repetition.

The evolving concept of physiological ischemia training vs. ischemia preconditioning.

Ischemic heart diseases are the leading cause of death with increasing numbers of patients worldwide. Despite advances in revascularization techniques, angiogenic therapies remain highly attractive. Physiological ischemia training, which is first proposed in our laboratory, refers to reversible ischemia training of normal skeletal muscles by using a tourniquet or isometric contraction to cause physiologic ischemia for about 4 weeks for the sake of triggering molecular and cellular mechanisms to promote angiogenesis and formation of collateral vessels and protect remote ischemia areas. Physiological ischemia training therapy augments angiogenesis in the ischemic myocardium by inducing differential expression of proteins involved in energy metabolism, cell migration, protein folding, and generation. It upregulates the expressions of vascular endothelial growth factor, and induces angiogenesis, protects the myocardium when infarction occurs by increasing circulating endothelial progenitor cells and enhancing their migration, which is in accordance with physical training in heart disease rehabilitation. These findings may lead to a new approach of therapeutic angiogenesis for patients with ischemic heart diseases. On the basis of the promising results in animal studies, studies were also conducted in patients with coronary artery disease without any adverse effect in vivo, indicating that physiological ischemia training therapy is a safe, effective and non-invasive angiogenic approach for cardiovascular rehabilitation. Preconditioning is considered to be the most protective intervention against myocardial ischemia-reperfusion injury to date. Physiological ischemia training is different from preconditioning. This review summarizes the preclinical and clinical data of physiological ischemia training and its difference from preconditioning.

Effect of low-frequency rTMS on aphasia in stroke patients: a meta-analysis of randomized controlled trials.

BACKGROUND: Small clinical trials have reported that low-frequency repetitive transcranial magnetic stimulation (rTMS) might improve language recovery in patients with aphasia after stroke. However, no systematic reviews or meta-analyses studies have investigated the effect of rTMS on aphasia. The objective of this study was to perform a meta-analysis of studies that explored the effects of low-frequency rTMS on aphasia in stroke patients. METHODS: We searched PubMed, CENTRAL, Embase, CINAHL, ScienceDirect, and Journals@Ovid for randomized controlled trials published between January 1965 and October 2013 using the keywords "aphasia OR language disorders OR anomia OR linguistic disorders AND repetitive transcranial magnetic stimulation OR rTMS". We used fixed- and random-effects models to estimate the standardized mean difference (SMD) and a 95% CI for the language outcomes. RESULTS: Seven eligible studies involving 160 stroke patients were identified in this meta-analysis. A significant effect size of 1.26 was found for the language outcome severity of impairment (95% CI = 0.80 to 1.71) without heterogeneity (I2 = 0%, P = 0.44). Further analyses demonstrated prominent effects for the naming subtest (SMD = 0.52, 95% CI = 0.18 to 0.87), repetition (SMD = 0.54, 95% CI = 0.16 to 0.92), writing (SMD = 0.70, 95% CI = 0.19 to 1.22), and comprehension (the Token test: SMD = 0.58, 95% CI = 0.07 to 1.09) without heterogeneity (I2 = 0%). The SMD of AAT and BDAE comprehension subtests was 0.32 (95% CI = -0.08 to 0.72) with moderate heterogeneity (I2 = 32%,P = 0.22). The effect size did not change significantly even when any one trial was eliminated. None of the patients from the 7 included articles reported adverse effects from rTMS. CONCLUSIONS: Low-frequency rTMS with a 90% resting motor threshold that targets the triangular part of the right inferior frontal gyrus (IFG) has a positive effect on language recovery in patients with aphasia following stroke. Further well-designed studies with larger populations are required to ascertain the long-term effects of rTMS in aphasia treatment.

Dynamic change of hydrogen sulfide during global cerebral ischemia-reperfusion and its effect in rats.

Hydrogen sulfide (H(2)S) is a gaseous messenger and serves as an important neuromodulator in central nervous system. In the current study, we investigated the change of H(2)S and cystathionine beta-synthase (CBS), an H(2)S-synthesizing enzyme at different time points of reperfusion following global cerebral ischemia in rats, and the effect of exogenous H(2)S on global cerebral ischemia-reperfusion injury. First, we used global cerebral ischemia-reperfusion model by occlusion of bilateral common carotid arteries and vertebral arteries. Next, we measured H(2)S levels in the hippocampus, cortex and plasma, the activity of H(2)S-synthesizing enzymes and expression of CBS mRNA and protein in the hippocampus and cortex at 12 h, 24 h, 48 h, 72 h and 7 days of reperfusion following 15 min cerebral ischemia. Second, we pretreated rats with different doses of sodium hydrogen sulfide (NaHS), an H(2)S donor and observed its effect on neuronal injury induced by 7 days of reperfusion after 15 min global cerebral ischemia. We found that when compared to sham group the amount of H(2)S in the hippocampus was increased significantly at 12 h of reperfusion after cerebral ischemia, markedly decreased at 24 h, restored to the same level as that in sham group at 48 h and maintained at 72 h and 7 days. The same change tendency in the levels of H(2)S was found in the cortex as described for the hippocampus. We found a similar change tendency in the activity of H(2)S-synthesizing enzymes, CBS mRNA and protein expression to that in the H(2)S level at different time points of reperfusion. Furthermore, while 180 micromol/kg NaHS pretreatment deteriorated the neuronal injury after global cerebral ischemia, 25 micromol/kg NaHS attenuated the neuronal injury. We suggest that a decrease of H(2)S level at 24 h of reperfusion after global cerebral ischemia may be involved in neuronal injury after cerebral ischemia and lower concentration rather than higher concentration of exogenous H(2)S may offer a protection against the neuronal injury induced by global cerebral ischemia-reperfusion.