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Poststroke cognitive impairment: diagnosis and treatment November 2019
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Efficacy of non-invasive brain stimulation interventions on cognitive impairment: an umbrella review of meta-analyses of randomized controlled trials
Journal of NeuroEngineering and Rehabilitation volume 22, Article number: 22 (2025)
Abstract
Background
The impact of noninvasive brain stimulation (NIBS) on cognitive and mental outcomes in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) remains under debate due to contradictory findings from systematic reviews and meta-analyses (SRMAs). To synthesize evidence from SRMAs assessing the effectiveness of NIBS techniques on cognitive and mental outcomes in AD and MCI populations. By comparing our findings to recent reviews and clinical guidelines, we highlight how this study addresses current limitations in the literature, provides a more holistic perspective on NIBS interventions, and guides future research and clinical practice.
Methods
We searched four databases from inception to May 15, 2024, reviewing SRMAs that analyzed the effects of NIBS. Effect sizes, 95% confidence intervals (CIs), and prediction intervals were computed for each meta-analysis. The methodological quality of the SRMAs was evaluated using the Measurement Tool to Assess Systematic Reviews 2, and the quality of evidence was assessed through the Grading of Recommendations, Assessment, Development, and Evaluation criteria.
Findings
Ten SRMAs detailing 22 associations were analyzed, focusing on two NIBS techniques across 12 unique outcomes. Significant improvements were observed in global cognition, language, executive function, and memory. Repetitive transcranial magnetic stimulation (rTMS) significantly enhanced short-term global cognition (standardized mean difference [SMD], 0.44; 95% CI 0.02–0.86), language (SMD, 1.64; 95% CI 1.22–2.06), executive function (SMD, 1.64; 95% CI 0.18–0.83), and long-term global cognition (SMD, 0.29; 95% CI 0.07–0.50). Transcranial direct current stimulation (tDCS) was effective in improving memory (SMD, 0.60; 95% CI 0.32–0.89) and executive function (SMD, 0.39; 95% CI 0.08–0.71). NIBS interventions showed no significant correlation with neuropsychiatric symptoms but demonstrated good tolerability in terms of safety and acceptability.
Interpretation
This umbrella review indicates that NIBS techniques, particularly rTMS and tDCS, can significantly improve cognitive functions such as global cognition, language, executive functions, and memory in patients with AD and MCI. Despite potential benefits, results should be interpreted cautiously due to study heterogeneity and methodological limitations. Future studies should investigate their long-term effects and applicability across dementia types.
Graphical Abstract
Introduction
With an increasing aging population, dementia has become an urgent global public health challenge. According to the World Health Organization, approximately 55 million people worldwide are diagnosed with dementia annually, and this number is expected to rise to 82 million by 2030, with 60–70% of cases attributed to Alzheimer's disease (AD) [1]. AD is a chronic progressive neurodegenerative disease characterized by persistent cognitive decline [2] and neuropsychiatric symptoms (NPS) [3] that severely affect quality of life. Mild cognitive impairment (MCI) represents the transitional state from normal aging to AD, affecting 10–15% of the population aged > 65 years [4]. Approximately 30–40% of people with MCI, especially with memory difficulties, progress to AD and other forms of dementia within five years of diagnosis [5]. The Alzheimer's Association estimates that by 2023, the total expenditure for treating AD and other types of dementia will reach $345 billion [6]. The gradual functional impairment of patients with AD imposes significant costs on society and healthcare systems. Therefore, managing, preventing, and treating MCI and AD to reduce their incidence and healthcare costs represent current challenges.
Standard interventions for AD currently involve pharmacological treatments, specifically acetylcholinesterase inhibitors and N-methyl-D-aspartate antagonists [7]. However, these medications are associated with strong side effects and poor compliance, and therapeutic outcomes often fail to deliver satisfactory results. Non-invasive brain stimulation (NIBS) is a cost-effective supplementary and alternative therapeutic approach frequently used to treat MCI and age-related neurodegenerative diseases [8, 9]. The most widely used NIBS techniques for AD and MCI treatment include repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). Mechanistically, rTMS uses strong magnetic fields to generate focal currents through a coil to stimulate the brain, which can activate or inhibit neural activity in specific brain areas through high- or low-frequency stimulation, respectively [10, 11]. Conversely, tDCS delivers low-intensity electrical currents via electrodes on the scalp, modulating synaptic transmission by altering the polarization of the neuronal membrane, thereby promoting or inhibiting the generation of neural signals. It is worth noting that other TMS protocols (e.g., theta-burst stimulation) and transcranial electrical stimulation modalities (e.g., transcranial alternating current stimulation and transcranial random noise stimulation) are less frequently employed in clinical trials or routine care, possibly due to their less well-defined mechanisms and the absence of standardized treatment guidelines.
However, systematic reviews and meta-analyses (SRMAs) on the effect of NIBS interventions on cognitive function and neuropsychiatric symptoms in patients with MCI or AD have yielded varying results [12]. The reliability of study outcomes, which may be affected by reporting biases and inadequate statistical power due to small sample sizes, remains a key issue in NIBS research. Additionally, variations in inclusion and exclusion criteria, analytical methods, and risk of bias in SRMAs can lead to inconsistent results and conclusions. These factors may have contributed to the over-representation of significant findings in SRMAs. Furthermore, most SRMAs focus solely on one type of intervention (either rTMS or tDCS) and on specific domains (cognitive function or apathy) [2], which hampers a comprehensive understanding of the subject. Moreover, recent guidelines and reviews often do not integrate findings across different NIBS modalities and a range of cognitive and mental health outcomes, leaving gaps in the literature and unanswered questions regarding the comparative and collective value of these interventions.
Umbrella reviews are valuable tools for synthesizing evidence; identifying, integrating, and evaluating evidence from published SRMAs; and assessing the strength and validity of the evidence based on sample size, effect size, and biases [13, 14]. In this umbrella review, we systematically and comprehensively assessed the relationship between NIBS and cognitive and mental outcomes to provide evidence-based decision-making support to clinicians and rehabilitation specialists.
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