Abstract
Alzheimer's disease (AD) is a common neurodegenerative disease characterized by progressive memory loss and cognitive dysfunction and is the most common cause of dementia. In recent years, transcranial magnetic stimulation (TMS) has been widely used in the treatment of AD and has achieved better therapeutic results. In this study, from the perspective of bibliometrics, we used VOSviewer and CiteSpace software to visualize and analyze the research progress of TMS in AD in terms of scientific knowledge mapping, and to systematically review the current status and trend of the global research on TMS in the treatment of AD, in order to provide references and guides for future research in this field. Our bibliometric analysis of 605 publications (1999–2024) reveals three pivotal findings: The Italy dominate TMS-AD research output; repetitive transcranial magnetic stimulation (rTMS) targeting the precuneus and dorsolateral prefrontal cortex (DLPFC) shows consistent cognitive benefits; Emerging technologies are reshaping therapeutic precision. Intermittent theta burst stimulation as an emerging TMS stimulation mode is gradually becoming a future research direction. In the future, more attention will be paid to individualized therapeutic solutions and more precise stimulation with the help of neuronavigation to improve the therapeutic effect of TMS.
Keywords
Introduction
Alzheimer's disease (AD) represents a progressive neurodegenerative disorder marked by irreversible declines in memory, cognitive capacities, and behavioral autonomy. 1 Pathological conditions such as AD are often associated with severe memory deficits. 2 Transcranial magnetic stimulation (TMS) was proposed by Barker and colleagues based on the principles of electromagnetic induction discovered by Faraday in the nineteenth century. TMS induces an electric field in the brain by generating a magnetic field through a current-carrying coil, which can depolarize neurons and trigger the firing of action potentials. 3 TMS can be categorized into several types based on the stimulation pattern: single-pulse transcranial magnetic stimulation (sTMS), pair-pulse transcranial magnetic stimulation (ppTMS), theta burst stimulation (TBS), and repetitive transcranial magnetic stimulation (rTMS). TMS protocols exert differential neuromodulatory effects: High-frequency rTMS (≥5 Hz) enhances cortical excitability through long-term potentiation (LTP)-like plasticity, while low-frequency rTMS (≤1 Hz) and continuous theta-burst stimulation (cTBS) induce inhibitory effects resembling long-term depression (LTD). TMS is known for its high safety, good patient tolerability, and minimal side effects. 4 Common side effects include transient headache and scalp discomfort; serious adverse events (e.g. seizures). Over recent years, TMS has shown promising clinical efficacy in the treatment of AD as it continues to evolve.
Current AD therapies (e.g. cholinesterase inhibitors, NMDA antagonists) offer symptomatic relief but limited disease-modifying effects. TMS provides a noninvasive, well-tolerated alternative with modulatory effects on synaptic plasticity and network connectivity. Unlike pharmacotherapies, TMS avoids systemic side effects and can be precisely targeted to affected circuits (e.g. precuneus, DLPFC), making it a promising adjunctive therapy.
Through the bibliometric analysis of the field, the development trend and dynamics of a certain field can be visualized, reflecting the current research hotspots and cutting-edge directions. 5 At present, there are more studies on TMS in AD, but there are fewer studies related to analyzing the hotspots and trends of TMS in AD from the perspective of visual analysis. We analyze the related studies of TMS in AD using the VOSviewer and CiteSpace software and draw visual maps to reveal the field's development history, research hotspots, and development trends, and provide references for the research application of TMS in AD. While recent bibliometric studies have analyzed TMS in AD, 6 our study extends this work by: using dual analytical tools (VOSviewer + CiteSpace) to capture nuanced trends; and focusing on mechanistic insights (synaptic plasticity, hippocampal modulation) and emerging technologies (closed-loop TMS, fMRI-DTI guidance). At present, while studies like have broadly examined noninvasive brain stimulation in AD through bibliometrics, 7 our work specifically targets TMS interventions, leveraging a more extensive dataset (605 publications from 1999–2024) and dual-software analysis (VOSviewer and CiteSpace) to identify unique mechanistic and clinical trends. This study aims to address two key questions: What are the global research trends and knowledge gaps in TMS for AD? How can emerging technologies overcome current limitations in TMS clinical translation?
Methods
Data sources
Published papers were retrieved via on the Web of Science core collection database, and the literature was screened from Science Citation Index Expanded (SCI-EXPANDED) (1999-present), Social Sciences Citation Index (SSCI) (1999–2021), The search terms are topic search = (“Transcranial Magnetic Stimulation*” OR “Theta burst stimulation” OR TMS OR rTMS OR iTBS OR aTMS OR cTBS) AND topic search = (“Alzheimer's Disease” OR “Alzheimer Disease”), The time span for the search was set from January 1999 to December 8, 2024. The search was limited to published papers in English and included Article and Review as document types. Records were excluded if they: were not in English; lacked full-text access; focused on non-AD populations (e.g. Parkinson's disease); were editorials or conference abstracts; duplicate records were identified using DOI/PMID matching and removed prior to analysis. An initial search of 672 relevant records were identified, and 621 published papers were obtained by removing other types of published papers. By reading the titles and abstracts of the articles, 5 articles and 11 reviews that were not related to the research topic were removed. After the above screening process, 605 published papers were finally included, from which data such as country, institution, author, journal, keywords, and citation information were extracted for bibliometric analysis.
Research tools
This study mainly used VOSviewer and Citespace software for bibliometric analysis. VOSviewer is a visual analysis tool introduced by Van Eck and Waltman from Leiden University, The Netherlands in 2009. VOSviewer (V1.6.19) is used to perform a visual analysis of the country, institution, author, keyword, literature co-citation, and journal co-citation. The parameters configured in VOSviewer are adjusted according to the actual situation. Citespace was created in 2004 by Dr Chaomei Chen and his team at Drexel University in Philadelphia, USA, using time-based and graphical visualization and analysis tools. It can present the development trend and structural relationship of scientific knowledge, visualize the development trend and dynamics of a certain field, and reflect the current research hotspots and cutting-edge directions. Keyword clustering analysis, keyword emergence, and journal biplot overlay analysis were performed using CiteSpace (V.6.3.R1). The parameters of CiteSpace software were set as follows: time slicing (1 year), K = 25, the network pruning method was the Pathfinder method, and the keyword clustering was done using the Log-Likelihood Ratio (LLR) clustering algorithm.
Results
Annual number of publications
A total of 605 records were retrieved from the WOSCC database, comprising 412 (68%) articles and 193 (32%) reviews. Figure 1 shows the number and trend of annual publications related to TMS and AD from 1999 to 2024. Overall, the number of publications shows an increasing trend and has grown at a faster rate with more articles in recent years, peaking in 2022 with the number of publications, and the trend is likely to continue in the future as TMS technology continues to evolve in the field.
Number of annual publications from 1999 to 2024.
Countries/regions
The analysis results show that the country with the largest number of articles is Italy (N = 179), followed by China (N = 147) and the United States (N = 140). Detailed information of the top 10 countries/regions in terms of the number of articles is shown in Table 1. In terms of centrality, the centrality of the United States (0.48), Spain (0.33), Germany (0.29), and the United Kingdom is high, which indicates that it maintains close cooperation with other countries/regions, as shown in Figure 2. The country/region evolution graph shows that China has had more publications in the last two years. Italy is the country that started the research in this field earlier and has sent more publications in the early years, as shown in Figure 3. From the heat of the issue graph, Italy, the United States, and China have higher research heat and have achieved better research results in this field, as shown in Figure 4.
Cluster-based countries/regions collaboration map. Cluster-based countries/regions collaboration map. Nodes: Countries/regions; Node size: Publication volume; Node color: Cluster affiliation (collaboration groups); Lines: Collaborative links between countries; Line thickness: Collaboration strength.
Time-based countries/regions collaboration map.
Publication density map.
Top 10 countries/regions in terms of the number of publications.
Centrality quantifies a node's importance as a network bridge (betweenness centrality), calculated as the fraction of shortest paths passing through it.
Institutions
Harvard University (N = 50) is the most prolific and influential institution in this domain. Next in line are IRCCS Santa Lucia (N = 49) and Harvard Medical School (N = 42). Boston University (0.29), Harvard Medical School (0.24), and Johns Hopkins University (0.2) are the top three centrality institutions, signifying strong collaboration and interaction with other institutions. Comprehensive details of the top 10 institutions based on publication volume and centrality are provided in Table 2. The institutional collaboration network illustrates that nodes of the same color are institutions with close connections, as indicated in Figure 5. The time-based institutional collaboration graph was presented in Figure 6, captures the temporal evolution of institutional publications, with Harvard University and IRCCS San Raffaele Pisana pioneering the field, and Harvard Medical School becoming a dominant force in recent years. Over the last two years, Harvard Medical School has notably increased its publication output in this field. The institutional hotspot map was presented in Figure 7, reveals that IRCCS Santa Lucia, Harvard Medical School, and the University of Brescia have a heightened focus on this area of research.
Cluster-based institutional collaboration map.
Time-based institutional collaboration map.
Institutional density map.
Top 10 institutions in terms of the number of publications.
Authors
Among the issuing authors, the highest number of publications is found in Giacomo Koch (N = 43), followed by Alessandro Martorana (N = 23). The author network diagram shows that some of the authors form close collaborative teams with closer ties to each other, as shown in Figure 8. In terms of centrality, the authors with high centrality are Claudio Babiloni (0.07), followed by Giacomo Koch (0.05), and the top 10 authors in terms of number of publications and centrality are shown in Table 3.
Cluster-based author collaboration map.
Top 10 authors in terms of the number of publications.
Keyword analysis
Keyword co-occurrence analysis. Keyword co-occurrence analysis can intuitively and comprehensively understand the research hotspots and trends in this field, as shown in Figure 9, the statistical results show that from the point of view of the frequency of the keywords, AD occurs most frequently; followed by TMS, mild cognitive impairment, dementia, etc. In terms of the centrality of the keywords, the keyword with the highest centrality is amyloid beta, followed by brain, apolipoprotein E, dementia, alternating current stimulation etc. The top 10 keywords in terms of frequency of occurrence and centrality are shown in Table 4. From the keyword analysis, it can be seen that rTMS is currently more widely application in patients with AD, and the main dysfunctions of concern are dementia and memory function impairment. According to the centrality of the keywords, the research on the mechanism of action of TMS to improve cognitive function in AD patients and the site of brain stimulation are the hotspot of research.
Cluster-based keywords collaboration map.
Top 10 keywords of word frequency.
Keyword clustering analysis. The clustering analysis of high-frequency keywords was performed by the LLR algorithm in Citespace software, and 10 representative keyword clustering labels were obtained, as shown in Figure 10. The LLR algorithm identifies clusters by maximizing the probability of keyword co-occurrence within groups. Modularity (Q) measures cluster separation robustness (Q > 0.3 = significant structure), while Silhouette (S) quantifies intra-cluster homogeneity (S > 0.5 = reliable clustering). Our values (Q = 0.4463; S = 0.7498) confirm robust clustering. Stability was assessed via 10 iterations with random seeds; cluster labels remained consistent (±5% variation). The value of Modularity in the plot is 0.4463 > 0.3 and the value of Mean Silhouette is 0.7498 > 0.5, which indicates that the clustering is efficient. The clustering keywords are detailed in Table 5. According to the results of keyword clustering analysis, rTMS is the commonly used intervention method. In terms of mechanism of action research, more attention is paid to neuromodulation, functional connectivity, pairwise correlated stimulation, and long-term potential differences. the hippocampus gradually became a stimulation site with higher attention to improving memory. The keyword clusters (e.g. ‘iTBS,’ ‘synaptic plasticity’) align with the broader shift toward precision medicine in AD research. For instance, intermittent burst stimulation (iTBS) protocols are increasingly tailored to individual neurophysiological profiles, mirroring biomarker-driven therapeutic strategies. Similarly, terms like ‘neuronavigation’ and ‘functional connectivity’ reflect the integration of multimodal neuroimaging to optimize stimulation targets, a hallmark of precision neurology. Future studies could leverage these trends to develop genotype- or phenotype-specific TMS protocols.
Keywords cluster map.
Keywords cluster labels and main keywords.
Silhouette value: Measures cluster cohesion (range: −1 to 1; values >0.5 indicate strong homogeneity).
Keyword timeline chart. The keyword timeline graph can show the hotspots and trends in the research field through the historical evolution of keywords, as shown in Figure 11. The keyword timeline graph shows that the keywords that started research earlier in the field are clustered into studies on rTMS, the hippocampus and long-term potential difference. The latest research hotspots focus on studies in the areas of transcranial direct current stimulation, neuromodulation, functional connectivity, paired-associative stimulation, and long-term potential differences.
Timeline view of keywords.
Keyword bursts. The analysis of keyword emergence reflects the changes and trends in the focus of the research field, and the red part marks the time when each keyword appears. Strength in the keyword emergence graph represents the strength of keyword emergence; the larger the value represents the greater the strength of the emergence, as shown in Figure 12, in which the emergent words with higher attention are motor cortex excitability (2002–2014), circuits (2004–2014), electromagnetic tomography low resolution brain electromagnetic tomography (LORETA) (2004–2013), human motor cortex (2005–2018), Alzheimer's disease (2008–2019), the motor cortex (2009–2015), cortical plasticity (2013–2020). The emergent words that have appeared in the last two years are impairment (2022–2025), rTMS (2023–2025).
Keyword bursts.
Highly cited analysis
Taking the cited literature as a node, the literature data were analyzed for literature with high citation, as shown in Figure 13. The top 10 most frequently cited literature are shown in Table 6. Highly cited literature often represents high-impact literature in the field. Highly cited literature and high centrality literature mainly explore the latest research progress within the field. Comprehensive analysis of the cited literature shows that the stimulation technique with higher attention is rTMS, and the hotspot of the current research mainly focuses on the mechanism of TMS to improve the cognitive function of AD patients, and the stimulation parts with more attention are the cortical and precuneus stimulation of the brain, and the main direction of the research on the cortical stimulation is the research on the cortical excitability and the cortical plasticity. The most cited papers, such as Koch et al., pioneered precuneus-targeted rTMS for memory enhancement. 8 Similarly, Lefaucheur et al. established rTMS safety guidelines yet lacked AD-specific protocols. 9 While these works catalyzed mechanistic research, their limitations highlight the need for longitudinal trials and multidisciplinary frameworks to bridge preclinical findings to clinical practice.
Cluster-based co-citation literature collaboration map.
The top 10 cited literature.
Journal co-citation
Journal co-citation analysis of the literature data from the Web of Science core ensemble database using cited journals as nodes is shown in Figure 14. The top 5 journals in terms of citation frequency are shown in Table 7. The journal with the highest frequency of citations is Neurology (N = 429, IF = 7.7). The journal with the highest centrality is Annual Review of Neuroscience (0.1, IF = 12.1). The majority of the combined cited journals were in the medical and neurological categories.
Cluster-based journal co-citation collaboration map.
Top 10 cited journals.
Journal overlay
The dual mapping overlay of journals shows the position of a research topic relative to the major research disciplines, visualizing the research dynamics of the disciplines through the flow of information at the journal level, see Figure 15. The dual mapping overlay of journals consists of two main parts: the citing journals on the left and the cited journals on the right. There are four main citation paths in the journal bitmap overlay. The yellow path indicates that journals in the field of molecular/biology/immunology are typically influenced by journals in the fields of molecular/biology/genetics (z = 5.6567507, f = 6752) and psychology/education/sociology (z = 3.077585, f = 3856). The gray path indicates that journals in the fields of Neurology/Kinesiology/Ophthalmology are influenced by journals in the field of Molecular/Biology/Genetics (z = 3.2610476, f = 4062) and Psychology/Education/Social (z = 2.632287, f = 3356).The z-score (z) reflects the statistical significance of a citation path (higher z = stronger association), and frequency (f) denotes observed citation counts along that path.
The dual-map overlay of journals.
Discussion
Current status of research
Over the past decade, the annual number of publications in the research of TMS in AD has been on an overall upward trend, and the annual number and trend of publications related to TMS and AD from 1999 to 2024 show an increasing trend in the number of publications, and the growth rate is faster and the number of publications is higher in recent years, with the number of publications peaking in 2022. With the continuous upgrading of technology, more and more stimulation mode will be applied in the research and clinical treatment of AD. The future research on TMS in AD is likely to maintain a relatively stable growth trend. In terms of the countries that published articles, the country with the largest number of articles is Italy, with a total of 179 articles, followed by the United States and China, with 140 and 137 articles, respectively. In terms of centrality, the centrality of the United States (0.48), and China has a higher number of publications in the past two years. Italy is the country that started the research in this field earlier and has issued more publications in the early years. In terms of institutions, Harvard University is the most publications and influential institution in this field. This is followed by IRCCS Santa Lucia and Harvard Medical School with 49 and 42 papers, respectively. Boston University, Harvard Medical School, and Johns Hopkins University are the top three institutions in terms of centrality, indicating closer communication and collaboration between the institution and other institutions. Harvard University and IRCCS San Raffaele Pisana initiated research in this area in the early years, and Harvard Medical School has become a dominant force in recent years. Harvard Medical School has published a high number of papers in this field in the last two years. These institutions have advanced experimental equipment and rich academic resources, which facilitate in-depth relevant research in this field and actively engage in exchanges and cooperation with other countries and institutions to promote TMS research within the field of AD.
In terms of the authors’ publications, the highest number of papers was published by Giacomo Koch (N = 43), followed by Alessandro Martorana (N = 23). The author network diagram shows that some of the authors form close collaborative teams with closer ties to each other. In terms of centrality, the authors with higher centrality are Claudio Babiloni (0.07), followed by Giacomo Koch (0.05). Giacomo Koch and the team of researchers focused on the clinical efficacy of TMS of different modalities and intensities on the improvement of cognitive function in patients with AD and the related mechanisms of action. Alessandro Martorana and his team focused on the pathological changes in brain tissue and biomarkers in AD patients and conducted a series of studies on the use of TMS in AD.
In terms of total citations to journals, the journal with the highest citation frequency is Neurology (N = 429 citations, IF = 7.7), which is highly authoritative in the field of Neurology, mainly by presenting the latest basic and clinical research in the field of Neurology. The journal with the highest centrality is Annual Review of Neuroscience (0.1, IF = 12.1), which mainly covers major developments in the entire field of neuroscience. The majority of the cited journals are in the medical and neurological categories.
Research hotspots and trends
Keyword analysis can intuitively and comprehensively understand the research hotspots and trends in the field and provide directions for future research. 18 In this publications, through the analysis of keyword co-occurrence, keyword clustering, and keyword emergence, it is found that the current research hotspots mainly focus on the effects of rTMS on cognitive and memory functions of AD patients, the clinical practice focuses on the application of TMS in different cortical areas of the brain, and the effects of TMS on synaptic plasticity and hippocampal function are paid attention to in the study of the mechanism of action. Intermittent theta burst stimulation as an emerging TMS stimulation mode is gradually becoming a future research direction.
Effects of rTMS on cognitive and memory functions in AD patients. Among several stimulation modes of TMS, rTMS is the TMS stimulation protocol with the highest frequency in keyword co-occurrence. rTMS refers to the delivery of a series of TMS pulses at a certain frequency and intensity, which can cause a change in the excitability of the brain, and such a change can last a period of time after the stimulation. rTMS is applied to the patient's head through a coil and uses brief but powerful electromagnetic pulses to alter brain activity. 19 Burst stimulation had an inhibitory effect on brain activity. Related studies have shown that rTMS improves general cognitive function in patients with mild-to-moderate AD 13 and can improve memory and executive function in patients with mild cognitive impairment and AD. 10 According to the results of keyword co-occurrence, the current research on the mechanism of action of rTMS is the current research hotspot. In animal experiments, Chen X et al. performed rTMS on APP/PS1 mice at a frequency of 5 Hz for 2 weeks and found that rTMS could improve cognitive impairment by decreasing the expression of p-Tau, amyloid-ß precursor protein (APP), Aβ, and PP2A and thus improving cognitive deficits in mice. 20 By treating APP23/PS45 double transgenic mice with low-frequency rTMS for 2 weeks, low-frequency rTMS reduced APP and its C-terminal fragments (CTFs) in the hippocampus, including C99 and C89, as well as β-site APP cleaving enzyme 1 (BACE1), which resulted in improved spatial learning and memory function. 21 rTMS, in addition to reducing Aβ deposition in 5xFAD mice, also improves the drainage efficiency of brain clearance pathways through the lymphatic system, parenchymal, and meningeal lymphatics. 22 The results of a clinical trial by Junwu Zhao 12 and others showed that rTMS improved cognitive function, memory, and language level in AD patients, especially for mild AD patients.
Research application of TMS in different cortical areas of the brain. At present, it is a research hotspot to explore the effects of TMS on the function of different cortical areas in the brain of AD patients, and the stimulation sites that have received more attention are the precuneus and prefrontal cortex (DLPFC). The precuneus is considered to be a key area for memory impairment in early AD, and patients with AD usually show reduced thickness of the precuneus cortex, accompanied by abnormal activity during memory tasks and decreased functional connectivity, which affects cognitive and memory functions. 23 Koch 8 and others conducted a 2-week clinical trial on 14 patients with early AD. The results of the study showed that rTMS to the precuneus region of the brain improved the situational memory function of the patients, and the analysis of the TMS-EEG signals showed an increase in neural activity in the midbrain region, an enhancement of the beta band oscillations, and an alteration of the functional connectivity between the midbrain region and the medial frontal region. Moreover, Koch 8 and others found that rTMS in the precuneus induced improvements in situational memory function, and TMS-EEG signal analysis showed increased neural activity in the precuneus, enhanced beta-band brain oscillations, and altered functional connectivity between the precuneus and the medial frontal region of the default mode network (DMN). The results of a meta-analysis showed that rTMS significantly improved cognitive performance in patients with mild-to-moderate AD, and that multi-site stimulation and long-term treatment improved AD-related cognitive performance, and the precuneus may be a more effective therapeutic site for improving memory in AD. 13 The dorsolateral prefrontal cortex (DLPFC), which is mainly responsible for cognitive functions, such as executive functioning and working memory, 24 plays an important role in the neural network of AD patients, and the DLPFC is also responsible for cognitive functions, such as executive functioning and working memory. 24 Relevant studies have shown that rTMS stimulation of the DLPFC can change the cognitive functions of AD patients. 25 The accuracy and reaction time of lexical processing in AD-type dementia patients can be improved by 10 Hz rTMS stimulation of the bilateral dorsolateral prefrontal cortex in AD patients. 26 And high-frequency rTMS stimulation of the left and right DLPFC five times a day improved cognitive function in patients with mild to moderate AD. 14
Impact of TMS on regulating aspects of synaptic plasticity. As can be seen from the keyword emergence, there has been a greater focus on the cerebral cortex and synaptic plasticity in recent years. Synaptic plasticity is the ability to form new connections between brain nerve cells or persistent changes in the strength of connections between existing connections, 27 which mainly consists of two manifestations: LTP and LTD, both of which are coordinated. the coordinated expression of the two is the basis for normal learning and memory. 28 Relevant studies have shown that impaired cortical plasticity in AD patients can lead to cognitive decline, 29 and rTMS can increase cortical excitability and plasticity. 30 Pathological alterations in tau protein have been associated with mechanisms of LTD-like cortical plasticity and cognitive decline, and tau protein levels in the cerebrospinal fluid may have an impact on cortical plasticity in AD patients. 31 Amyloid antibodies can inhibit synaptic plasticity of cortical transmission. 21 Animal studies have found that rTMS at 25 Hz can improve cognitive function, reduce hippocampal Aβ1–42 levels, ameliorate oxidative stress, improve glucose metabolism in 3xTg-AD model mice, attenuate neuroinflammatory responses in AD patients through activation of the PI3K/Akt/GLT-1 pathway, enhance synaptic plasticity, and reduce neuronal loss and apoptosis. 32 20 Hz of rTMS early intervention can ameliorate early neuroinflammation and improve synaptic plasticity in 5xFAD mice by activating the PI3K/Akt/NF-KB signaling pathway. 33 In the clinic, TMS-based cortical assessment techniques can predict the disease progression of dementia function and memory function in AD patients by LTP-like cortical plasticity. 15
Effects of TMS on hippocampal function in AD patients. The effect of TMS on hippocampal function in AD patients has attracted greater attention in recent studies. The hippocampus is crucial in the formation, organization, storage and transmission of new memories, especially in the process of converting short-term memories into long-term memories. At the same time, the hippocampus is closely related to cognitive functions and has rich nerve fiber connections with the prefrontal cortex and other brain regions. Early AD is accompanied by hippocampal atrophy, leading to functional disconnection from other brain regions, especially the parietal cortex. 34 Moreover, LTP function is seriousness impaired in AD patients, especially in the hippocampal CA1 region. 35 Targeting the hippocampal network, rTMS can modulate synaptic plasticity by promoting LTP function in order to improve memory dysfunction. rTMS can also improve cognitive function in AD patients by increasing functional connectivity between the hippocampus and precuneus. 36 In an animal experiment, brain-derived neurotrophic factor (BDNF) and phosphorylated CREB were significantly elevated in mice after stimulation by high-frequency rTMS at 5 Hz and activated the BDNF/CREB pathway in the hippocampus, which modulated the plasticity of hippocampal synaptic structures and improved cognitive dysfunction in naturally aging mice. 37 The use of low-frequency rTMS modulated the excitability and high-frequency firing of hippocampal neurons in a mouse model of AD. 38 rTMS increased the expression of the dopamine DR4 gene and BDNF in the cerebral cortex and hippocampus of a mouse model of AD 39 and improved the level of hippocampal N-Acetyl-L-aspartic acid in patients with ADA in order to accelerate the process of neuronal healing. It was found that rTMS could have considerable effects on the integrity and metabolism of hippocampal neurons and play an obvious role in neuroprotection. 40 However, as the hippocampus is located in the deep part of the brain, there are certain challenges in using TMS to stimulate the hippocampus. Currently, personalized functional MRI (fMRI) guidance methods can be used in the clinic to effectively enable TMS stimulation to reach the hippocampus. A clinical trial based on resting-state fMRI with high-frequency rTMS stimulation of the left parietal region with the highest functional connectivity to the hippocampus showed that. fMRI-guided rTMS treatment improved cognitive function and increased dynamic functional connectivity of the default mode network in AD patients in the short term. 41
Research applications of intermittent theta-burst stimulation in AD. TBS is a TMS stimulation modality that has emerged in recent years, and TBS can modulate cortical excitability more effectively. 42 TBS usually consists of triple-pulse pulses at 50 Hz, repeated at 5 Hz, for a total of 600–1800 pulses. 43 TBS protocols can be used to induce cortical plasticity in the brain and can modulate neural activity. Currently, TBS mainly consists of two protocols, iTBS and continuous pulse stimulation (cTBS). iTBS performs stimulation for 190 s in a 2-s on, 8-s off pattern, while cTBS performs continuous stimulation for 40 s. 44 Currently, the iTBS protocol is more widely used in clinical practice. iTBS is an accelerated excitatory rTMS parameter consistent with endogenous oscillations. Compared with conventional rTMS, iTBS is more effective in improving neuroplasticity, especially LTP plasticity, in the left DLPFC. 45 White matter connectivity between superficial stimulation sites and the hippocampus in cognitively impaired patients can be improved by a single iTBS treatment. 46 iTBS can ameliorate cognitive deficits and attenuate neuroinflammation by activating the PI3K/Akt/mTOR signaling pathway. 47 By treating 6-month-old APP/PS1 mice with iTBS for 30 consecutive days, it was found that iTBS treatment could reduce the Aβ load in the cerebral cortex and hippocampus of APP/PS1 mice, and iTBS treatment was able to attenuate neuroinflammation, neuronal apoptosis, and synaptic loss in APP/PS1 mice. 48
Clinical implications and challenges of TMS in AD
The bibliometric and mechanistic insights from this study highlight the translational potential of TMS in AD management, yet several clinical considerations must be addressed to optimize its real-world application. Current evidence supports rTMS protocols targeting the precuneus or DLPFC as effective strategies for improving cognitive function in mild-to-moderate AD patients. 8 High-frequency rTMS (e.g. 10–20 Hz) applied to the precuneus enhances default mode network connectivity, correlating with memory improvement, whereas DLPFC stimulation may augment executive functions through frontoparietal network modulation. 25 However, standardized protocols remain elusive. Future studies should establish consensus on stimulation parameters (frequency, intensity, session duration) and evaluate multimodal approaches, such as combining rTMS with cognitive training or pharmacotherapy. Heterogeneity in treatment response underscores the need for biomarker-guided patient selection. For instance, baseline Aβ/tau levels in cerebrospinal fluid or plasma may predict TMS efficacy, as synaptic plasticity modulation by TMS is influenced by AD pathology. 36 Additionally, neuroimaging markers (e.g. hippocampal atrophy severity, functional connectivity patterns) could stratify patients for personalized targeting. A recent trial demonstrated that fMRI-guided rTMS improved outcomes in AD patients with preserved hippocampal-cortical connectivity, 42 However, rigorous longitudinal studies are needed to assess rare adverse events and neurodegeneration modulation. Clinical adoption of TMS faces practical barriers: High-end TMS devices (e.g. MRI-guided systems) are expensive, limiting accessibility in low-resource settings. Optimal outcomes require trained personnel for accurate coil positioning and parameter adjustment. Inter-Individual Variability: Response heterogeneity, influenced by genetic factors (e.g. APOE ε4 status) or comorbidities, necessitates adaptive protocols. Addressing these challenges requires collaborative efforts among researchers, clinicians, and policymakers to standardize protocols, reduce costs, and integrate TMS into multidisciplinary AD care pathways. Beyond AD, TMS has FDA approval for major depressive disorder (MDD) and obsessive-compulsive disorder (OCD), with protocols like Stanford's SAINT demonstrating high remission rates in MDD via fMRI-guided targeting. However, TMS carries seizure risks, necessitating rigorous screening (e.g. epilepsy history, medications). Other risks include transient headaches and hearing changes (requiring ear protection).
Emerging technologies to enhance TMS precision and personalization
Recent advancements in neurotechnologies are revolutionizing TMS applications in AD, addressing critical limitations such as inter-individual variability and suboptimal targeting. Closed-loop TMS integrates real-time neurophysiological feedback (e.g. EEG or local field potentials) to dynamically adjust stimulation parameters. For instance, EEG-guided closed-loop systems detect cortical excitability states and deliver TBS only during specific oscillatory phases (e.g. gamma oscillations), enhancing synaptic plasticity modulation. 47 Such systems may mitigate response variability by adapting to individual neurodynamics. Combining fMRI with diffusion tensor imaging (DTI) enables precise targeting of functionally connected networks. For example, fMRI identifies regions with aberrant DMN connectivity, while DTI maps white matter tracts (e.g. cingulum bundle) to optimize coil placement. 49 Jung et al. reported that fMRI-DTI-guided rTMS targeting the parietal-hippocampal pathway significantly improved episodic memory in AD patients (p < 0.01), whereas non-navigated stimulation showed no effect. 36 Machine learning algorithms analyze multimodal data (e.g. neuroimaging, genomics, clinical profiles) to predict optimal stimulation parameters. Additionally, reinforcement learning models can iteratively optimize stimulation intensity and frequency based on real-time cognitive performance metrics. 45 These tools may enable fully personalized protocols, reducing trial-and-error in clinical practice. Despite these innovations, barriers remain that Multimodal navigation and AI models require interdisciplinary expertise and computational resources.
Innovativeness
This study to visualize and analyze the research progress of TMS in AD from the perspective of bibliometrics by using VOSviewer and CiteSpace software, and to comprehensively analyze the research hotspots and future trends in this field from multiple perspectives, Unlike a single review article, the article analyzes the mechanism of TMS in improving cognitive and memory functions in AD patients from three aspects: the effect of TMS on different cortical regions of the brain, the effect of TMS on synaptic plasticity, and the effect of TMS on the hippocampus function of patients with AD, to comprehensively demonstrate the focus of the research in this field.
Limitations
Firstly, the research data included in this study came from the Web of Science Core Collection database, due to the limitations of the analysis software, one database was used for foreign literature, the language was limited to English, and the literature in other databases and other languages was not included, so the research content and hotspots reflected may not be able to cover all the content in this field, and a certain degree of bias may exist; secondly, the included literature was not subjected to a Secondly, there is no quality evaluation of the included literature, and the quality of the included literature may vary, which may have some influence on the analysis results. Keyword clustering may not fully capture mechanistic focus; future studies should validate trends with primary literature.
Conclusion
Our bibliometric analysis (1999–2024) reveals accelerating interest in TMS for AD, dominated by the USA, Italy, and China. Key institutions (Harvard University, IRCCS Santa Lucia) and authors (Koch, Martorana) drive research. rTMS targeting the precuneus/DLPFC consistently improves cognition, while emerging technologies (closed-loop TMS, fMRI-DTI guidance) and protocols (iTBS) promise enhanced precision. Future work must standardize protocols, leverage biomarkers for personalization, and address accessibility barriers. TMS remains a potent noninvasive tool for modulating AD-related network dysfunction.
Footnotes
Acknowledgements
We would like to thank Van Eck and Prof. Chaomei Chen for developing the VOSviewer and CiteSpace software.
Author contribution(s)
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: China Medical Qigong Society Youth Training Program (No.2025-Z0H-0NRC).
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.