Effects of cerebellar intermittent theta-burst stimulation on patients with Alzheimer's disease: A randomized controlled trial

Abstract

Background

The cerebellum plays a crucial role in cognitive processing, making it a potential target for therapeutic intervention in Alzheimer's disease (AD).

Objective

This study aimed to investigate the effect of cerebellar intermittent theta-burst stimulation (iTBS) in patients with AD.

Methods

We conducted a randomized, double-blind, sham-controlled clinical trial in which patients were randomly allocated to receive either active-iTBS or sham-iTBS. The primary outcome was the change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores from baseline to week 4. Secondary outcomes included evaluations of neurophysiological measures, brain network functions, and glymphatic clearance.

Results

From April 20 to June 25, 2024, 20 patients were analyzed. Compared with sham-iTBS, active-iTBS significantly improved cognition at week 4, indicated by reduced CDR-SB scores (mean changes: −0.60 versus 0.15; adjusted β: 0.73; 95% CI, 0.17–1.26). In the active-iTBS group compared with the sham-iTBS group, the power spectral density in electroencephalogram revealed global decreased in theta power (adjusted β, −0.014; 95% CI, −0.024–0.003) and increased beta power (adjusted β, 0.002; 95%CI, 0.000–0.005), the functional magnetic resonance imaging demonstrated enhanced the gradient values of default mode network activity along the principal gradient, and the structural magnetic resonance imaging indicated an improvement in glymphatic clearance (adjusted β, 0.097, 95% CI, 0.0381–0.1603).

Conclusions

A four-week course of iTBS improved cognitive function in patients with AD, possibly via promoting the Beta frequency band power, enhancing brain network functionality, and facilitating glymphatic clearance.

Trial registration

ClinicalTrials.gov (NCT06379100, April 14, 2024).

Keywords

Alzheimer's disease brain connectivity cerebellum glymphatic clearance intermittent theta burst stimulation transcranial magnetic stimulation

Introduction

AD is a progressive neurodegenerative disease that poses substantial challenges for both families and society.¹ Drug therapy for AD includes symptomatic treatments (acetylcholinesterase inhibitors and N-methyl-D-aspartate receptors antagonists) and disease-modifying therapies (DMTs) targeting amyloid-beta (Aβ) and Tau protein.^2–4 However, traditional medications only relieve symptoms without stopping the disease from progressing,⁵ while the DMTs are expensive and not widely available.⁴ Therefore, it is crucial to explore safe and effective non-drug therapy.⁶

Repetitive transcranial magnetic stimulation (rTMS) as a physical therapy has showed considerable potential in treating AD.^7–10 Recently study showed rTMS targeting the cerebellar crus II region enhanced cognitive performance in AD patients by strengthening functional connectivity with prefrontal cortex.¹¹ The cerebellum plays a crucial role in cognitive processes, connecting and modulating circuits between the thalamus, cortex, and limbic system.^12–14 The cerebellum has been proposed as a key node for modulating cognitive function.^15,16 For instance, closed-loop connections between the cerebellum and the dorsolateral prefrontal cortex support executive control and working memory, while pathways linking the right Crus I region to Broca's area via the dentato-thalamo-cortical tract facilitate language processing.^15,17 Additionally, cerebellar-parietal networks mediate spatial attention,¹⁴ and vermis-limbic circuits regulate emotional processing.¹⁸ Beyond these functional roles, the cerebellum exhibits a capacity for cognitive resilience, termed cerebellar cognitive reserve (CCR), which arises from synaptic plasticity and dynamic neural reconfiguration.^19,20 This reserve manifests in compensatory cerebellar engagement observed in neurodegenerative conditions: for example, studies have reported inverse correlations between cerebellar Aβ metabolism and cortical Aβ burden in AD, suggesting a protective role.²¹ Similarly, in mild cognitive impairment, cerebellar hyperactivation alongside disrupted cerebro-cerebellar connectivity (particularly within DMN and FPN) reflects adaptive neural strategies to maintain cognition despite pathology.²² CCR is thus activated under conditions of neurodegeneration or aging, where it may buffer against cognitive decline by strengthening alternative neural pathways. Cerebellar stimulation has been suggested as a potential treatment to enhance this reserve, highlighting cerebellum as a neuromodulation target for cognitive networks.

In this study, we conducted a randomized, double-blind, sham-controlled clinical trial to assess the efficacy and potential mechanisms of cerebellar iTBS in treating AD patients, with neuronavigation system based on three-dimensional reconstruction to target cerebellar lobule VII, oriented toward the cerebellar dentate nucleus (CDN).

Methods

Trial design and oversight

This study was a prospective, randomized, double-blind, sham stimulation, parallel controlled clinical trial. We conducted this trial at the Neurology Department of Xijing Hospital. The trial protocol was approved by ethics committees of Xijing Hospital (KY20244082-1) and detailed in Supplemental File 1. All procedures in this study were in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. The trial was registered at ClinicalTrials.gov (NCT06379100) on April 14, 2024.

Patients

Patients were enrolled between April 20, 2024 and June 25, 2024, with the final follow-up at August 25, 2024. Patients were eligible if they 1) aged 50 to 80 years old, 2) met the diagnostic criteria of AD,^23,24 and the cerebrospinal fluid (CSF) biomarkers showed a decrease in Aβ and an increase in phosphorylated tau (p-tau) protein, 3) the Mini-Mental State Examination (MMSE) score ranged from 18–26 points, and the Clinical Dementia Rating (CDR) score ranged from 0.5–1 points, 4) had at least one adult caregiver, 5) had been treated with acetylcholinesterase inhibitors (AChEI) and/or memantine at least 3 months. Patients were excluded if they had other types of dementia, history of epilepsy, psychotic disorders, cerebrovascular diseases, contraindications to TMS or MRI. Details of inclusion and exclusion criteria were displayed in Supplemental Table 1. The written consents were obtained from patients or their legally authorized representatives before study entry.

Randomization and masking

Patients were randomly assigned with a 1:1 ratio to 2 intervention arms: active-iTBS group or sham-iTBS group. The randomization sequence was generated by computer (SAS Statistical Package, version 9.2) and prepared by an independent statistician. The randomization sequence was generated by computer (SAS Statistical Package, version 9.2) and prepared by an independent statistician. A pilot study where 7 patients were asked to guess their group allocation after treatment. The questionnaire included three options: Real Stimulation, Sham Stimulation, and Uncertain. Five patients selected “Uncertain”. Furthermore, patients wore noise-cancelling headphones to minimize auditory disturbance from TMS. All participants were TMS-naïve. The independent operators signed confidentiality agreements before the initiation of the trial and were isolated in separate rooms during sessions. The grouping results were blinded to all participants and investigators except the TMS deliverer, who did not participate in other parts of the trial. Our results were conducted by an independent statistical analysis team, who did not participate in other parts of the study.

Trial procedures

During the screening stage, all participants underwent baseline assessments of cognitive and functional performance, resting state electroencephalogram (EEG) recordings, and MRI scans. Demographics and clinical characteristics were also recorded. Three visits were scheduled at the outpatient clinic of the Neurology Department in Xijing Hospital, and the data of corresponding evaluation were collected. The visit at week 0 (W0) was conducted within 48 h before the initiation of TMS treatment, and the visit at week 4 (W4) was conducted within 24 h after the final completion of TMS treatment. The visit at week 8 (W8) was conducted after 4 weeks from the end of TMS treatment (Figure 1).

Figure 1.

Experimental design and methods. Clinical evaluation, 64-channel EEG and MRI were performed at baseline (W0), after 4 weeks of treatment (W4). The clinical evaluation and MRI were repeated at 4 weeks after the end of treatment (W8) (a). Brain function was evaluated with 64 channel-EEG and MRI, and lymphatic drainage was analyzed by the index of DTI-ALPS and CP/ICV of MRI (b). CP/ICV: Choroid plexus relative to the intracranial volume; DTI-ALPS: Diffusion tensor image analysis along the perivascular space; EEG: electroencephalogram; iTBS: intermittent theta burst stimulation; MRI: magnetic resonance imaging.

The delivery of TMS

The patients were in a sitting position during treatment. Navigated active-iTBS or sham-iTBS targeting cerebellum was delivered via a Neuro-MS/D TMS stimulator (Neurosoft, GTMEDI Technology Co. Ltd Beijing, China) connected to a double-cone coil, once daily during workdays over a 4-week treatment period, resulting in 20 sessions in total (Supplemental Figure 1). A frameless neuro-navigation system based on 3-dimensional reconstruction of individual MRI data (Brain Science Tools BV, Utrecht, the Netherlands) was used to ensure the coil to pass through the cerebellum VIIb and focus on the CDN (Supplemental Figure 2). Continued feedback was provided throughout the entire stimulation session via the navigation system to ensure precise targeting. Single-pulse TMS was applied to the dominant thumb motor cortex to determine resting motor threshold (RMT), defined as the minimum intensity required to elicit visible thumb abductor movement in ≥50% of trials (5/10 pulses). Active stimulation consisted of 600 pulses (3 pulses at 50 Hz, repeated at 5 Hz for 200 ms). Cerebellar iTBS was delivered bilaterally in four blocks (left-right-left-right, 5-min intervals), totaling 1200 stimuli per hemisphere per session. Over 20 sessions (4 weeks), each patient received 48,000 stimuli. Sham stimulation replicated active parameters but with the coil tilted 90° (edge contacting scalp) to mimic auditory effects without neural activation. Noise-cancelling headphones minimized TMS-related auditory interference. The detailed stimulation procedure was described in the Supplemental Material.

Data collection

At W0, demographics, family history, course of disease, laboratory tests, clinical scores (MMSE, Hamilton Depression Scale [HAMD], Hamilton Anxiety Scale [HAMA], CDR-SB, Neuropsychiatric Inventory [NPI], Activities of Daily Living [ADL], AD Assessment Scale-Cognition [ADAs-cog]), CSF biomarkers, resting state EEG and head MRI results were recorded. At W4, the clinical scores, resting state EEG and head MRI were repeated. At W8, the clinical scores and head MRI were repeated again. The concomitant medication, adverse events (AEs), and serious AEs (SAEs) were documented throughout the study.

At W0 and W4, the resting state EEG were performed with a 64-channel gel electrode cap (GT Cap PRO, GreenTek, Wuhan, China). The MRI images were performed with a 3.0 T MRI scanner (uMR 780, United Imaging Healthcare, Shanghai, China) for each participant. The images of fMRI (blood oxygen level dependent functional magnetic resonance imaging [BOLD]) were performed at W0 and W4. The images of sMRI (T1-weighted imaging and T2-weighted imaging) and Diffusion Tensor Imaging (DTI) were performed at W0 and week W8. The information of EEG and MRI was detailed in the Supplemental Material.

Electroencephalogram analysis

The electroencephalogram analysis was conducted using resting state EEG. The power spectral density (PSD) was employed to analyze brain activity using Welch method in different EEG frequency bands: delta (0.5–4 Hz), theta (4–8 Hz), alpha (8–13 Hz), beta (13–30 Hz). The unit of the PSD is μV²/Hz. The weighted phase lag index (wPLI) was used to calculate brain connectivity. The EEG signal preprocessing was conducted with the EEGLab tool-box in Matlab R2023b25 (Supplemental Material).

Functional MRI analysis

The Regional Homogeneity (ReHo) was employed to assess the activity patterns of local brain regions.²⁶ Given the central role of the default mode network (DMN) in the pathology of AD,^27,28 we concentrated on brain regions associated with the DMN. Subsequently, we analyzed the functional connectivity (FC) between the DMN and other brain networks. Finally, we observed hierarchical improvements of the DMN through functional connectivity gradients. Further details were provided in the Supplemental Material.

Glymphatic clearance analysis

To evaluate glymphatic clearance, the images of DTI and T1 were used to calculate the DTI-ALPS, which evaluates glymphatic system function by quantifying directional water diffusion along cerebral perivascular spaces.²⁹ The ALPS index is derived from standardized ratios of diffusion anisotropy between projection fibers (x-axis) and association fibers (y-axis), serving as an indirect biomarker of glymphatic clearance efficiency.³⁰ The DTI-ALPS using MRtrix3 and FMRIB software Library (FSL) version 6.0 for the computations. FreeSurfer software package (version 7.1.1) was employed to automatically segment the volume of choroid plexus (CP) and intracranial volume (ICV) from T1-weighted images.^31,32 Additionally, a skilled radiologist thoroughly examined and corrected the segmentations of the CP and ICV. The specific procedure was described in Supplemental Figure 3.

Outcomes

The primary efficacy outcome was the changes of CDR-SB from W0 to W4 between active-iTBS group and sham-iTBS group. The secondary outcomes included the changes of scores on MMSE, ADAs-cog, ADL, NPI, the changes of PSD and wPLI in EEG, and the changes of Reho, FC and functional gradients analysis in fMRI from W0 to W4. The changes of scores on CDR-SB, MMSE, ADAs-cog, ADL, NPI, and the changes of DTI-ALPS and Choroid plexus relative to the intracranial volume (CP/ICV) in sMRI from W0 to W8 were also analyzed. Safety outcomes included the incidence of TMS intolerance, AEs and SAEs throughout the study.

Statistical analysis

In this exploratory study, patients were analyzed according to the principle of intention-to-treat (ITT). As a clinical exploratory study, we set a sample size of 20 patients. Continuous variables were expressed as descriptive statistics (mean with standard deviation [SD] or median with interquartile range [IQR]). Categorical variables were summarized as counts and percentages. Baseline clinical characteristics were compared between the groups using the Student's t-test, Wilcoxon test, or Fisher's exact test, as appropriate. Clinical outcomes were analyzed using general linear models (bootstrap analysis), which were adjusted for age, gender, and education duration. To evaluate the impact of treatment on clinical outcomes over time, generalized estimating equations were used to compare changes in clinical outcomes, which were adjusted for age, gender, education duration and baseline scores. For all between-group analyses, interaction effects were assessed first, with main effects analysis results reported only in the absence of significant interactions. The details of analyses on EEG and MRI were displayed in the Supplemental Material. Two-sided p values < 0.05 in all tests were considered significant. Statistical analyses were carried out using SPSS (version 23), R (version 4.3.0), and the DPABI toolbox (v8.3) in MATLAB.

Results

Study population

Between April 20, 2024 to June 25, 2024, 28 patients were screened for eligibility. Of these, 20 patients were randomized into two group: 10 in the active-iTBS group and 10 in the sham-iTBS group (Figure 2). Details of the enrolled patients were demonstrated in Supplemental Table 2. The mean age of the patients was 62 years, with SD of 7 (range 50 to 76), and 50% were female. Baseline characteristics, including demographics, course of disease, family history, cognitive decline severity, and CSF biomarkers were similar between groups (Table 1). All randomized patients completed the treatment period, and no patients withdrew from the trial (Figure 2).

Figure 2.

CONSORT flow diagram for randomization of patients with AD.

Table 1.

Baseline demographics and clinical characteristics.

	Active-iTBS (n = 10)	Sham-iTBS (n = 10)
Age, years, mean (SD)	61 (5)	64 (9)
Gender (female), n (%)	4 (40%)	6 (60%)
Education, years, mean (SD)	11.5 (2.9)	11.5 (3.2)
Disease duration, years, mean (SD)	3.3 (1.4)	3.7 (2.1)
Family history of dementia, n (%)	1 (10%)	1 (10%)
Clinical Scale
CDR-SB, mean (SD)	6.40 (0.66)	6.50 (0.71)
MMSE, mean (SD)	18.30 (1.42)	19.00 (3.30)
ADAs-cog, mean (SD)	23.80 (2.74)	23.90 (2.73)
ADL, mean (SD)	26.54 (5.78)	27.10 (6.17)
NPI, mean (SD)	12.20 (4.59)	10.90 (6.97)
HAMD, mean (SD)	4.13 (3.34)	3.60 (2.01)
HAMA, mean (SD)	4.53 (1.92)	3.70 (2.41)
CSF biomarkers
Aβ₁₋₄₂, pg/ml, mean (SD)	491.3 (53.1)	533.1 (49.1)
Aβ₁₋₄₀, pg/ml, mean (SD)	9244 (1201)	7505 (1392)
Aβ₁₋₄₂/Aβ₁₋₄₀	0.07 (0.02)	0.06 (0.13)
p-tau 181, pg/ml, mean (SD)	175.60 (8.8)	149.35 (18.9)
Glymphatic clearance
DTI-ALPS, mean (SD)	1.19 (0.94)	1.22 (0.17)
CP/ICV, mean (SD)	0.0016 (0.00038)	0.0018 (0.00017)

Aβ: amyloid-β; ADAs-cog: Alzheimer's disease Assessment Scale-Cognition; ADL: Activities of Daily Living; CDR-SB: Clinical Dementia Rating-Sum of Boxes; CP/ICV: Choroid plexus relative to the intracranial volume; DTI-ALPS: Diffusion tensor image analysis along the perivascular space; iTBS: intermittent theta-burst stimulation; HAMD: Hamilton Depression Scale; HAMA: Hamilton Anxiety Scale; iTBS: intermittent theta-burst stimulation; MMSE: Mini-Mental State Examination; NPI: Neuropsychiatric Inventory; SD: standard deviation.

Clinical outcomes

The baseline scores of CDR-SB were comparable between the two groups, a decline in scores was observed at weeks 4 and 8 (Table 1, Supplemental Table 3). Compared to the sham-iTBS group, patients treated with active-iTBS showed significantly lower scores of CDR-SB (adjusted mean difference, −0.76; 95% CI, −1.32 – −0.21) with a significant time-dependent treatment effect (adjusted β, −0.86, 95% CI,- 1.31 – −0.42) (Figure 3). The primary outcome (changes of CDR-SB from W0 to W4) was −0.60 for active-iTBS group and 0.15 for the sham-iTBS group (adjusted β, 0.73; 95% CI, 0.17–1.26) (Figure 3, Supplemental Table 4). However, the treatment effect of active-iTBS on CDR-SB fell back during the follow-up at W8 (−0.15 versus 0.25; adjusted β, 0.45; 95% CI, −0.01–1.00) (Figure 3, Supplemental Table 5). In the sham-iTBS group, the cognitive functions showed a gradual deterioration, as evaluated by CDR-SB scores (Figure 3, Supplemental Tables 4 and 5).

Figure 3.

Clinical outcomes of patients. The changes of CDR-SB, ADAs-cog and MMSE from baseline (W0) to 4 weeks after treatment (W4), and 4 weeks after the end of the treatment (W8) in patients assigned to active-iTBS group and sham-iTBS group (a-c). The scores of CDR-SB between two groups at W0, W4, and W8 (d). All data of CDR-SB, ADAs-cog, MMSE, ADL and NPI at week 4 (W4, Left) and week 8 (W8, Right) were normalized changes relative to the baseline scores. The vertical axis of radar map is the percentage of improvement with outward movements (e). ADAs-cog: Alzheimer's Disease Assessment Scale-Cognition; ADL: Activities of Daily Living; CDR-SB: Clinical Dementia Rating-Sum of Boxes; iTBS: intermittent theta-burst stimulation; MMSE: Mini-Mental State Examination; NPI: Neuropsychiatric Inventory. *Statistically significant values (p < 0.05).

The baseline scores of ADAs-cog, MMSE, ADL and NPI did not differ between the two groups (Table 1). The scores of weeks 4 and 8 are summarized in Supplemental Table 3. Compared to sham-iTBS, active-iTBS demonstrated lower ADAS-cog scores (adjusted mean difference −3.22, 95% CI – 3.773 to −2.673; p < 0.001) and higher MMSE scores (adjusted mean difference + 4.755, 95% CI 2.743–6.766; p < 0.001), with significant time-dependent enhancement of treatment effects (adjusted β, 4.6, 95% CI, 2.75–6.45; adjusted β, −2.50, CI, −3.15 – −1.85) (Figure 3, Supplemental Tables 4 and 5). However, there were no differences in ADL and NPI scores between the two groups over time (Supplemental Figure 4, Supplemental Tables 4 and 5). The procedure was safe and well tolerated. Two patients (20%) in the active-iTBS group and 0 (0%) patients in sham-iTBS group reported AEs, both presenting with mild headaches that alleviated on the same day.

Electroencephalogram analysis

To evaluate the neurophysiological changes, the EEG PSD was analyzed between the two groups. After 4 weeks of treatment, the active-iTBS group showed lower global power at theta frequency band (adjusted β, −0.014; 95% CI, −0.024–0.003) and higher global power at beta frequency band (adjusted β, 0.002; 95% CI, 0.000–0.005) compared to the sham-iTBS group (Figure 4). There was no difference in delta and alpha frequency bands between the two groups (Figure 4). The maps of wPLI-derived connectivity for two groups indicated a decreased trend of delta and theta band connectivity, and an increased trend of beta band connectivity (Figure 4(e)).

Figure 4.

Electroencephalogram of patients. The changes of PSD in Delta, Theta, Alpha, and Beta from baseline (W0) to 4 weeks after treatment (W4) in patients assigned to active-iTBS group and sham-iTBS group (a-d). Topographic maps of electrode pairs in connectivity in Delta, Theta, Alpha and Beta frequency bands between active-iTBS group and sham-iTBS group from W0 to W4 (e). Data in the box-and-whiskers plots are median with interquartile range. Red lines indicate increase of brain connectivity, and blue lines indicate decrease of brain connectivity. iTBS: intermittent theta burst stimulation; PSD: power spectral density. wPLi: weighted phase lag index. *Statistically significant values (p < 0.05).

Functional MRI analysis

Compared to sham-iTBS group, patients treated with active-iTBS displayed an increase in ReHo within the right dorsolateral superior frontal gyrus cortex (F = 67.40; 95% CI, 0.02–0.42) and the right angular gyrus (F = 92.15, 95% CI, 0.05–0.42), both of which were components of the DMN regions (Supplemental Figure 5, Supplemental Table 6). In FC, we found decreases in inter-network connectivity of DMN-Ventral Attention Network (VAN), DMN-Dorsal Attention Network (DAN), and DMN-frontoparietal network (FPN) in the active-iTBS group (Supplemental Figure 6, Supplemental Table 7). In the functional gradients analysis, patients treated with active-iTBS displayed an increase of the gradient values of the DMN in the principal gradient compared to the sham-iTBS group, but the secondary gradient did not differ between groups (Figure 5(a)-(c), Supplemental Table 8). Finally, we found that the changes of CDR-SB score from baseline to W4 correlated with DMN variation of principal gradient in the active-iTBS (R = −0.77, 95% CI, −0.932–0.359) but not in the sham-iTBS group, showing that CDR-SB score improvement was paralleled by an increase of the gradient values of the DMN (Figure 5(d)).

Figure 5.

Functional MRI of patients. DMN in functional gradient scores between active-iTBS and sham-iTBS from baseline (W0) to 4 weeks (W4) after treatment (a-c). Correlation analysis performed between the changes of CDR-SB score and the changes of DMN principal functional gradient scores between two groups (d). Red color represents the F-value of the DMN function gradient analysis, and the darker the red color, the larger the F-value. DMN: default mode network; iTBS: intermittent theta-burst stimulation. *Statistically significant values (p < 0.05).

Glymphatic clearance analysis

The mean index of baseline DTI-ALPS (1.19 versus 1.22) and CP/ICV (0.0016 versus 0.0018) were similar between the active-iTBS group and sham-iTBS group (Table 1). After treatment, the mean DTI-ALPS index in the active-iTBS group increased to 1.301, which was higher than that in the sham-iTBS group of 1.215 (adjusted β, 0.097, 95% CI, 0.0381–0.1603), indicating that cerebellar iTBS could effectively improve glymphatic clearance (Figure 6(a)). However, there was no difference in CP/ICV between the two groups (Figure 6(b)).

Figure 6.

Lymphatic drainage of patients. The changes of the DTI-ALPS and CP/ICV from baseline (W0) to 4 weeks (W4) after treatment in patients assigned to active-iTBS group and sham-iTBS group (a-b). iTBS: intermittent theta burst stimulation; CP/ICV: Choroid plexus relative to the intracranial volume; DTI-ALPS: Diffusion Tensor Imaging Along the Perivascular Space. *Statistically significant values (p < 0.05).

Discussion

Our study shows that active-iTBS targeting cerebellar has a positive impact on cognitive function in patients with mild to moderate AD, as demonstrated by the reduction of scores in CDR-SB and ADAs-cog, along with an increase of scores in MMSE. Additionally, these changes are accompanied by an increase of Beta frequency band power in the EEG, improved glymphatic clearance in the sMRI, and an increase of DMN in the fMRI. Notably, AEs were mild and uncommon in patients treated with active-iTBS.

Unlike symptomatic treatments, which aim to alleviate cognitive or behavioral deficits, or DMT, which seek to slow or halt neurodegenerative processes, TMS does not fit neatly into either category.^2–4 TMS may exhibit symptomatic benefits and could influence disease-related mechanisms. It belongs to a broader class of non-pharmacological AD interventions to improve symptomatic relief and neuroprotective effects through targeted modulation of neural activity.³³ Cerebellar stimulation has demonstrated significant potential in the treatment of AD.¹¹ This stimulation differs from conventional stimulation targeting specific areas such as the dorsolateral prefrontal cortex (DLPFC) and precuneus,^7,8,10,34 by offering the advantages of modulating brain networks, enhancing CCR and strengthening cerebellum-brain connections.^11,20,35 In this study, we observed that active-iTBS significantly improved the cognitive function, as measured by the alterations of scores on CDR-SB, MMSE and ADAs-cog. Studies have reported similar improvement of cognitive function in iTBS targeting the DLPFC,³⁶ and rTMS targeting the cerebellar crus II in patients with AD.¹¹ However, our findings suggest a diminished efficacy of iTBS over time, which is in accordance with previous studies.^7,10,11 This highlights the necessity for longer interval TMS treatment to maintain its benefits.

Patients with mild AD often exhibits reduced Beta band activity and increased Theta band activity.^37,38 The abnormalities in the Theta band are closely linked to synaptic dysfunction and neural network desynchronization.^39,40 An increased Theta power has been associated with a decline in cognitive function, while a reduction may indicate the improvement in cognitive function.^41,42 Beta oscillations are essential for neural communication and memory processes, making them a useful tool for evaluating the effectiveness of AD treatments.^43,44 Studies have shown that increased Beta activity correlates with improved cognitive function,⁴⁵ which is utilized to evaluate the efficacy of AD treatment.^43,44 In our study, AD patients who underwent cerebellar iTBS treatment experienced a decrease in Theta band activity and an increase in Beta band activity across the brain. The changes suggest positive shifts in brain function that may lead to enhanced cognitive abilities.

The cerebellum plays a compensatory role in AD progression,⁴⁶ and stimulation of which can promote neural functional connectivity and plasticity.^11,47 In this study, the TMS coil was a double-cone coil with a stimulation depth of 4–6 cm, and the stimulation site included the VIIb lobule and CDN of the cerebellum. The VIIb lobule of the cerebellum is widely involved in advanced cognitive function.⁴⁸ The CDN is key for information transmission between cerebellum and cerebral cortex, broadly influencing cognitive functions.^49,50 And, the CDN is widely involved in the DMN connections, including links to prefrontal cortex, angular gyrus, and medial temporal lobe.⁵¹ In healthy individuals, DMN typically negatively correlates with some attention networks (ANs) and FPN, but these correlations are often abnormally increased in AD patients.^52–55 Our study used cerebellar iTBS targeting cerebellar, which significantly reduced FC between DMN and ANs, and DMN and FPN, which suggests that cerebellar iTBS may recover abnormal brain connectivity in AD patients. Additionally, previous studies have shown that AD patients had a lower DMN gradient values in first gradient compared to normal individuals.^31,56,57 In this study, cerebellar iTBS increased the gradient values of the DMN in first gradient of AD patients, which may indicate an improvement in brain function in AD patients. This is the first study to propose cerebellar iTBS to enhance cognition of AD patients and modulate DMN for cognitive improvement in AD patients.

The glymphatic system in the brain is crucial for waste clearance.^58,59 Damage to meningeal glymphatic vessels accelerates Aβ deposition and exacerbates AD progression.⁶⁰ Enhancing glymphatic clearance has been shown to improve cognitive outcomes.^61–63 AD patients exhibit a decreased DTI-ALPS index, whereas a higher DTI-ALPS index is linked to better cognitive function.⁶⁴ We found that active-iTBS treatment may effectively enhance glymphatic clearance, as demonstrated by the increased DTI-ALPS index, which was in line with a preclinical study of high-frequency TMS treatment.⁶⁵ Thus, the enhanced change of DTI-ALPS is a vital factor for the positive alteration of cognitive in patients treated with active-iTBS in our study.

There are some limitations in the present study. Firstly, the small sample size may limit the generalizability of the research findings. The findings should be considered preliminary, and future large-scale studies are required to validate both the therapeutic effects and underlying mechanisms. Secondly, the relatively short duration of active-iTBS may lead to the therapeutic effect not being sustained. Thirdly, the concentration of Aβ and p-tau in the CSF was not reassessed after the active-iTBS treatment. Nonetheless, this research represents a pioneering effort in utilizing iTBS to activate the cerebellum for the treatment of AD. Further studies with long-term therapeutic intervention and larger sample size should be taken into consideration in future research to fully assess the potential and mechanism of cerebellar iTBS.

In conclusion, our study suggests that cerebellar iTBS may improve cognitive function in AD patients after a 4-week period. This improvement was confirmed by increased beta frequency band power in the EEG and enhanced the gradient values of the DMN in the first gradient of the fMRI, and improved glymphatic clearance in the sMRI. However, we observed a decline in cognitive improvements at week 8. Therefore, further long-term intervention studies are warranted to verify the effectiveness and underlying mechanism of stimulating CCR in AD patients.

Supplemental Material

sj-docx-1-alz-10.1177_13872877251366656 - Supplemental material for Effects of cerebellar intermittent theta-burst stimulation on patients with Alzheimer's disease: A randomized controlled trial

Supplemental material, sj-docx-1-alz-10.1177_13872877251366656 for Effects of cerebellar intermittent theta-burst stimulation on patients with Alzheimer's disease: A randomized controlled trial by Xin Zhang, Zhongqing Sun, Dianwei Wu, Xiaojing Shi, Changgeng Song, Xiao Guan, Jianmin Hao, Yaomin Guo, Xiaorui Wang, Dong Wei, Zhirong Liu, Jingjing Zhao and Wen Jiang in Journal of Alzheimer's Disease

Supplemental Material

sj-docx-2-alz-10.1177_13872877251366656 - Supplemental material for Effects of cerebellar intermittent theta-burst stimulation on patients with Alzheimer's disease: A randomized controlled trial

Supplemental material, sj-docx-2-alz-10.1177_13872877251366656 for Effects of cerebellar intermittent theta-burst stimulation on patients with Alzheimer's disease: A randomized controlled trial by Xin Zhang, Zhongqing Sun, Dianwei Wu, Xiaojing Shi, Changgeng Song, Xiao Guan, Jianmin Hao, Yaomin Guo, Xiaorui Wang, Dong Wei, Zhirong Liu, Jingjing Zhao and Wen Jiang in Journal of Alzheimer's Disease

Supplemental Material

sj-pdf-3-alz-10.1177_13872877251366656 - Supplemental material for Effects of cerebellar intermittent theta-burst stimulation on patients with Alzheimer's disease: A randomized controlled trial

Supplemental material, sj-pdf-3-alz-10.1177_13872877251366656 for Effects of cerebellar intermittent theta-burst stimulation on patients with Alzheimer's disease: A randomized controlled trial by Xin Zhang, Zhongqing Sun, Dianwei Wu, Xiaojing Shi, Changgeng Song, Xiao Guan, Jianmin Hao, Yaomin Guo, Xiaorui Wang, Dong Wei, Zhirong Liu, Jingjing Zhao and Wen Jiang in Journal of Alzheimer's Disease

Footnotes

Acknowledgments

We thank all the investigators, participants, caregivers, and families who participated in this trial. We thank Dr Changsheng Chen for assistance with research design. We also thank Dr Shun Qi for MRI data analysis.

ORCID iDs

Xin Zhang

Zhongqing Sun

Dianwei Wu

Changgeng Song

Xiao Guan

Jianmin Hao

Yaomin Guo

Xiaorui Wang

Dong Wei

Zhirong Liu

Jingjing Zhao

Wen Jiang

Ethical considerations

The trial protocol was approved by the Ethics office of Xijing hospital (approval number, KY20242285).

Consent to participate

All participants or their representatives provided written informed consent before participation in the trial.

Author contributions

Xin Zhang: Conceptualization; Formal analysis; Methodology; Writing – original draft.

Zhongqing Sun: Methodology.

Dianwei Wu: Formal analysis; Methodology; Software.

Xiaojing Shi: Data curation; Software.

Changgeng Song: Investigation; Validation.

Xiao Guan: Formal analysis; Software.

Jianmin Hao: Methodology; Software.

Yaomin Guo: Methodology; Software.

Xiaorui Wang: Formal analysis; Software.

Dong Wei: Formal analysis; Supervision.

Zhirong Liu: Conceptualization; Methodology; Project administration; Supervision; Validation, Visualization.

Jingjing Zhao: Data curation; Project administration; Supervision; Validation; Writing – original draft.

Wen Jiang: Conceptualization; Funding acquisition; Investigation; Supervision; Visualization; Writing – review & editing.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was founded by Shaanxi Province Special Support Program for Leading Talents in Scientific and Technological Innovation (grant number tzjhjw), Clinical Research Program of the Fourth Military Medical University (2023LC2314). The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Supplemental material

Supplemental material for this article is available online.

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