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Cognitive Enhancement of Repetitive Transcranial Magnetic Stimulation in Patients With Mild Cognitive Impairment and Early Alzheimer's Disease: A Systematic Review and Meta-Analysis.

ABSTRACT: Repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technique, has been considered as a potentially effective treatment for the cognitive impairment in patients with mild cognitive impairment (MCI) and Alzheimer's Disease (AD). However, the effectiveness of this therapy is still under debate due to the variety of rTMS parameters and individual differences including distinctive stages of AD in the previous studies. The current meta-analysis is aiming to assess the cognitive enhancement of rTMS treatment on patients of MCI and early AD. Three datasets (PubMed, Web of Science and CKNI) were searched with relative terms and finally twelve studies with 438 participants (231 in the rTMS group and 207 in the control group) in thirteen randomized, double-blind and controlled trials were included. Random effects analysis revealed that rTMS stimulation significantly introduced cognitive benefits in patients of MCI and early AD compared with the control group (mean effect size, 1.17; 95% CI, 0.76 - 1.57). Most settings of rTMS parameters (frequency, session number, stimulation site number) significantly enhanced global cognitive function, and the results revealed that protocols with 10 Hz repetition frequency and DLPFC as the stimulation site for 20 sessions can already be able to produce cognitive improvement. The cognitive enhancement of rTMS could last for one month after the end of treatment and patients with MCI were likely to benefit more from the rTMS stimulation. Our meta-analysis added important evidence to the cognitive enhancement of rTMS in patients with MCI and early AD and discussed potential underlying mechanisms about the effect induced by rTMS.

SUBMITTER: Xie Y

PROVIDER: S-EPMC8461243 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionTranscranial magnetic stimulation (TMS) is a non-invasive intervention that holds promise for improving cognitive function in individuals with Alzheimer's disease (AD). However, the effectiveness of this therapy and the optimal TMS parameters has not reached a consensus. The purpose of the meta-analysis was to systematically discern the effectiveness of different components of TMS protocols on cognitive improvement in patients with mild cognitive impairment (MCI) and AD.MethodsThe meta-analysis was preregistered on Prospero (registration number: CRD42022345482). PubMed, Web of Science, Science Direct, and Cochrane Library databases were used to search, screen and identify eligible studies with the following keywords: Transcranial Magnetic Stimulation OR TMS OR theta burst stimulation AND Alzheimer OR Alzheimers OR Alzheimer's OR mild cognitive impairment OR MCI. Randomized controlled trials (RCTs) of participants with accepted standardized diagnostic criteria were searched by two authors independently. The risk of bias was assessed using an adapted Cochrane Risk of Bias tool. Standardized mean difference (SMD) and 95% confidence interval (CI) were calculated using the random-effects models. Subgroup analyses were performed to investigate the influential factors.ResultsA total of 21 studies and 25 trials were included in this meta-analysis. The findings revealed a significant overall cognition improvement of real stimulation compared with sham stimulation (short-term effects: SMD, 0.91; 95% CI 0.44-1.38; P < 0.01; long-lasting effects: SMD, 0.91; 95% CI 0.27-1.55; P < 0.01). Subgroup analysis demonstrated that stimulation of the left dorsolateral prefrontal cortex and bilateral cerebellums, as well as moderate frequency stimulation (5 Hz and 10 Hz) on mild and moderate cognitive impairment patients, were more effective than other TMS protocols. However, the additional application of cognitive training showed no significant improvement.ConclusionCognitive improvement effect of TMS was demonstrated in MCI and AD patients in both short-term assessment and long-lasting outcomes, and the efficiency of TMS is affected by the stimulation frequency, stimulation site, and participant characteristics. Further RCTs are needed to validate the findings of our subgroup analysis.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022345482, identifier: CRD42022345482.

Project description:Background: Mild cognitive impairment (MCI) is an early stage of Alzheimer's disease. Repetitive transcranial magnetic stimulation (rTMS) has been widely employed in MCI research. However, there is no reliable systematic evidence regarding the effects of rTMS on MCI. The aim of this review was to evaluate the efficacy and safety of rTMS in the treatment of MCI. Methods: A comprehensive literature search of nine electronic databases was performed to identify articles published in English or Chinese before June 20, 2019. The identified articles were screened, data were extracted, and the methodological quality of the included trials was assessed. The meta-analysis was performed using the RevMan 5.3 software. We used the GRADE approach to rate the quality of the evidence. Results: Nine studies comprising 369 patients were included. The meta-analysis showed that rTMS may significantly improve global cognitive function (standardized mean difference [SMD] 2.09, 95% confidence interval [CI] 0.94 to 3.24, p = 0.0004, seven studies, n = 296; low-quality evidence) and memory (SMD 0.44, 95% CI 0.16 to 0.72, p = 0.002, six studies, n = 204; moderate-quality evidence). However, there was no significant improvement in executive function and attention (p > 0.05). Subgroup analyses revealed the following: (1) rTMS targeting the left hemisphere significantly enhanced global cognitive function, while rTMS targeting the bilateral hemispheres significantly enhanced global cognitive function and memory; (2) high-frequency rTMS significantly enhanced global cognitive function and memory; and (3) a high number of treatments ?20 times could improve global cognitive function and memory. There was no significant difference in dropout rate (p > 0.05) between the rTMS and control groups. However, patients who received rTMS had a higher rate of mild adverse effects (risk ratio 2.03, 95% CI 1.16 to 3.52, p = 0.01, seven studies, n = 317; moderate-quality evidence). Conclusions: rTMS appears to improve global cognitive function and memory in patients with MCI and may have good acceptability and mild adverse effects. Nevertheless, these results should be interpreted cautiously due to the relatively small number of trials, particularly for low-frequency rTMS.

Project description:Individuals with amnestic mild cognitive impairment (aMCI) have a high risk of developing Alzheimer's disease. Although repetitive transcranial magnetic stimulation (rTMS) is considered a potentially effective treatment for cognitive impairment in patients with aMCI, the neuroimaging mechanisms are poorly understood. Therefore, we performed a double-blind randomized sham-controlled trial in which rTMS was applied to the left dorsolateral prefrontal cortex of aMCI patients recruited from a community near the Third Hospital Affiliated to Sun Yat-sen University, China. Twenty-four patients with aMCI were randomly assigned to receive true rTMS (treatment group, n = 12, 6 men and 6 women; age 65.08 ± 4.89 years) or sham stimulation (sham group, n = 12, 5 men and 7 women; age 64.67 ± 4.77 years). rTMS parameters included a stimulation frequency of 10 Hz, stimulation duration of 2 seconds, stimulation interval of 8 seconds, 20 repetitions at 80% of the motor threshold, and 400 pulses per session. rTMS/sham stimulation was performed five times per week over a period of 4 consecutive weeks. Our results showed that compared with baseline, Montreal Cognitive Assessment scores were significantly increased and the value of the amplitude of low-frequency fluctuation (ALFF) was significantly increased at the end of treatment and 1 month after treatment. Compared with the sham group, the ALFF values in the right inferior frontal gyrus, triangular part of the inferior frontal gyrus, right precuneus, left angular gyrus, and right supramarginal gyrus were significantly increased, and the ALFF values in the right superior frontal gyrus were significantly decreased in the treatment group. These findings suggest that high-frequency rTMS can effectively improve cognitive function in aMCI patients and alter spontaneous brain activity in cognitive-related brain areas. This study was approved by the Ethics Committee of Shenzhen Baoan Hospital of Southern Medical University, China (approval No. BYL20190901) on September 3, 2019, and registered in the Chinese Clinical Trials Registry (registration No. ChiCTR1900028180) on December 14, 2019.

Project description:BackgroundMild Cognitive Impairment (MCI) carries a high risk of progression to Alzheimer's disease (AD) dementia. Previous clinical trials testing whether cholinesterase inhibitors can slow the rate of progression from MCI to AD dementia have yielded disappointing results. However, recent studies of the effects of repetitive transcranial magnetic stimulation (rTMS) in AD have demonstrated improvements in cognitive function. Because few rTMS trials have been conducted in MCI, we designed a trial to test the short-term efficacy of rTMS in MCI. Yet, in both MCI and AD, we know little about what site of stimulation would be ideal for improving cognitive function. Therefore, two cortical sites will be investigated in this trial: (1) the dorsolateral prefrontal cortex (DLPFC), which has been well studied for treatment of major depressive disorder; and (2) the lateral parietal cortex (LPC), a novel site with connectivity to AD-relevant limbic regions.Methods/designIn this single-site trial, we plan to enroll 99 participants with single or multi-domain amnestic MCI. We will randomize participants to one of three groups: (1) Active DLPFC rTMS; (2) Active LPC rTMS; and (3) Sham rTMS (evenly split between DLPFC and LPC locations). After completing 20 bilateral rTMS treatment sessions, participants will be followed for 6 months to test short-term efficacy and track durability of effects. The primary efficacy measure is the California Verbal Learning Test-II (CVLT-II), assessed 1 week after intervention. Secondary analyses will examine effects of rTMS on other cognitive measures, symptoms of depression, and brain function with respect to the site of stimulation. Finally, selected biomarkers will be analyzed to explore predictors of response and mechanisms of action.DiscussionThe primary aim of this trial is to test the short-term efficacy of rTMS in MCI. Additionally, the project will provide information on the durability of cognitive effects and potentially distinct effects of stimulating DLPFC versus LPC regions. Future efforts would be directed toward better understanding therapeutic mechanisms and optimizing rTMS for treatment of MCI. Ultimately, if rTMS can be utilized to slow the rate of progression to AD dementia, this will be a significant advancement in the field.Trial registrationClinical Trials NCT03331796. Registered 6 November 2017, https://clinicaltrials.gov/ct2/show/NCT03331796. All items from the World Health Organization Trial Registration Data Set are listed in Appendix A.Protocol versionThis report is based on version 1, approved by the DSMB on 30 November, 2017 and amended on 14 August, 2018 and 19 September, 2019.

Project description:ObjectivePost-stroke cognitive impairment (PSCI) is resistant to treatment. Recent studies have widely applied repetitive transcranial magnetic stimulation (rTMS) to treat various brain dysfunctions, such as post-stroke syndromes. Nonetheless, a protocol for PSCI has not been established. Therefore, this study is aimed to evaluate the therapeutic effect of our high-frequency rTMS protocol for PSCI during the chronic phase of stroke.MethodsIn this prospective study, ten patients with PSCI were enrolled and received high-frequency rTMS on the ipsilesional dorsolateral prefrontal cortex (DLPFC) for 10 sessions (5 days per week for 2 weeks). Cognitive and affective abilities were assessed at baseline and 2 and 14 weeks after rTMS initiation. To investigate the therapeutic mechanism of rTMS, the mRNA levels of pro-inflammatory cytokines (interleukin (IL)-6, IL-1β, transforming growth factor beta [TGF-β], and tumor necrosis factor alpha [TNF-α]) in peripheral blood samples were quantified using reverse transcription polymerase chain reaction, and cognitive functional magnetic resonance imaging (fMRI) was conducted at baseline and 14 weeks in two randomly selected patients after rTMS treatment.ResultsThe scores of several cognitive evaluations, i.e., the Intelligence Quotient (IQ) of Wechsler Adult Intelligence Scale, auditory verbal learning test (AVLT), and complex figure copy test (CFT), were increased after completion of the rTMS session. After 3 months, these improvements were sustained, and scores on the Mini-Mental Status Examination and Montreal Cognitive Assessment (MoCA) were also increased (p < 0.05). While the Geriatric Depression Scale (GeDS) did not show change among all patients, those with moderate-to-severe depression showed amelioration of the score, with marginal significance. Expression of pro-inflammatory cytokines was decreased immediately after the ten treatment sessions, among which, IL-1β remained at a lower level after 3 months. Furthermore, strong correlations between the decrease in IL-6 and increments in AVLT (r = 0.928) and CFT (r = 0.886) were found immediately after the rTMS treatment (p < 0.05). Follow-up fMRI revealed significant activation in several brain regions, such as the medial frontal lobe, hippocampus, and angular area.ConclusionsHigh-frequency rTMS on the ipsilesional DLPFC may exert immediate efficacy on cognition with the anti-inflammatory response and changes in brain network in PSCI, lasting at least 3 months.

Project description:BackgroundThe development of diagnostic tools capable of accurately identifying the pathophysiology of mild cognitive impairment (MCI) has become a crucial target considering the claim that disease-modifying treatments should be administered as early as possible in the disease course. Transcranial magnetic stimulation (TMS) protocols have demonstrated analytical validity in discriminating different forms of dementia; however, its value in daily clinical practice in MCI subjects is still unknown.ObjectiveTo evaluate the clinical value of TMS compared to amyloid markers on diagnostic confidence and accuracy in MCI subjects, considering clinicians' expertise.MethodsOne hundred seven MCI subjects were included and classified as MCI-Alzheimer disease (MCI-AD), MCI-frontotemporal dementia (MCI-FTD), MCI-dementia with Lewy bodies (MCI-DLB), or MCI-other in a three-step process based on (i) demographic, clinical, and neuropsychological evaluation (clinical work-up); (ii) clinical work-up PLUS amyloidosis markers or clinical work-up PLUS TMS measures; and (iii) clinical work-up PLUS both markers. Two blinded neurologists with different clinical expertise were asked to express a diagnostic confidence for each MCI subgroup, and ROC curve analyses were performed at each step.ResultsThe addition of TMS markers to clinical work-up significantly increased the diagnostic confidence for MCI-AD (p?=?0.003), MCI-FTD (p?=?0.044), and MCI-DLB (p?=?0.033) compared to clinical work-up alone, but not for MCI-other (p?>?0.05). No significant differences between the add-on effect of TMS and the add-on effect of amyloid markers to clinical work-up were observed (p?>?0.732), while the diagnostic confidence further increased when both markers were available. The greater the clinical expertise, the greater the flexibility in considering alternative diagnosis, and the greater the ability to modify diagnostic confidence with TMS and amyloid markers.ConclusionsTMS in addition to routine clinical assessment in MCI subjects has a significant effect on diagnostic accuracy and confidence, comparable to well-established biomarkers of amyloidosis.

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Cognitive Enhancement of Repetitive Transcranial Magnetic Stimulation in Patients With Mild Cognitive Impairment and Early Alzheimer's Disease: A Systematic Review and Meta-Analysis.

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