Alzheimer's disease with depressive symptoms: Clinical effect of intermittent theta burst stimulation repetitive transcranial magnetic stimulation

Abstract

BACKGROUND

Alzheimer's disease (AD), characterized by the ongoing deterioration of neural function, often presents alongside depressive features and greatly affects the quality of life of individuals living with the condition. Although several treatment methods exist, their efficacy is limited. In recent years, repetitive transcranial magnetic stimulation (rTMS) utilizing the theta burst stimulation (TBS) mode, specifically the intermittent TBS (iTBS), has demonstrated promising therapeutic potential in the management of neuropsychiatric disorders.

AIM

To examine the therapeutic efficacy of iTBS mode of rTMS for treating depressive symptoms in patients with AD.

METHODS

This retrospective study enrolled 105 individuals diagnosed with AD with depressive symptoms at Huzhou Third Municipal Hospital, affiliated with Huzhou University, between January 2020 and December 2023. Participants received standard pharmacological interventions and were categorized into control (n = 53) and observation (n = 52) groups based on treatment protocols. The observation group received iTBS mode of rTMS, while the control group received pseudo-stimulation. A comparative analysis evaluated psychological well-being, adverse events, and therapeutic at initiation of hospitalization (T0) and 15 days post-treatment (T1).

RESULTS

At T1, both groups exhibited a marked reduction in self-rating depression scale and Hamilton depression scale scores compared to T0. Furthermore, the observation group showed a more pronounced decrease than the control group. By T1, the Mini-mental state examination scores for both groups had increased markedly from their initial T0 assessments. Importantly, the increase was particularly more substantial in the observation group than in the control group. Fourteen patients in the control group had ineffective treatment effects, while five patients in the observation group experienced the same. Additionally, the observation group experienced a substantially reduced incidence of ineffective treatment as compared to the control group (both P < 0.05); there were no recorded serious adverse events in either group.

CONCLUSION

The iTBS model of rTMS effectively treated AD with depression, improving depressive symptoms and cognitive function in patients without serious adverse reactions, warranting clinical consideration.

Key Words: Alzheimer's disease, Non-persistent θ short array fast pulse mode, Depression, Clinical efficacy, Dementia, Repetitive transcranial magnetic stimulation

Core Tip: Alzheimer's disease (AD) predominantly impacts brain neurons, being a chronic neurodegenerative condition. With disease progression, many patients with AD experience depressive symptoms, significantly impeding their lives while imposing a substantial strain on families and society. Therefore, this study investigated the clinical effects of repetitive transcranial magnetic stimulation-intermittent theta burst stimulation (iTBS-rTMS) on patients with AD experiencing depressive symptoms. Our findings suggest iTBS-rTMS significantly improves depressive symptoms and shows promise in enhancing cognitive function, offering a novel approach to managing comorbid depression in patients with AD and promoting the development of the field of neuroscience.

INTRODUCTION

Alzheimer's disease (AD) is a prevalent form of dementia that manifests as gradual deterioration of cognitive and behavioral skills due to degenerative lesions in the central nervous system. The core clinical symptoms include a decline in memory, comprehension, computation, orientation, self-care ability, and other aspects that are often accompanied by a decline in both cognitive and physical functions. It is characterized by insidious onset and progressive exacerbation[1,2]. With the progression of global population aging, there is an increasing concern about AD, which accounts for 60% to 80% of all dementia types[3]. Studies have shown that AD is associated with depression during disease progression[4]. Depressive symptoms accelerate the decline of cognitive function and self-care ability in patients with AD, profoundly impacting their overall quality of life and leading to heightened mortality and suicide rates[5]. Consequently, treating and managing depressive symptoms among patients with AD is crucial and should not be ignored. In the past, patients with AD and mood disorders were mainly treated with antidepressant medications, which could improve their mood, but were prone to side effects, leading to poor adherence to treatment[6,7]. Today, the effective treatment of AD is still a major problem plaguing scholars at home and abroad; therefore, actively seeking safe and effective alternative or adjunctive therapeutic measures for patients with AD is of great practical significance.

Repetitive transcranial magnetic stimulation (rTMS) is an electrophysiological therapy known for its precise positioning, minimal invasiveness, and painlessness, thereby effectively alleviating clinical symptoms in patients with depression[8]. However, this treatment also has shortcomings, such as a long stimulation time and treatment course, resulting in relatively low efficiency and low compliance. Theta burst stimulation (TBS) represents an innovative type of rTMS. Its advantage is that it can excite the cerebral cortex for a longer time under smaller stimulation intensities and times. Compared with conventional rTMS stimulation, this is more in line with the neuron discharge mode[9]. At the same time, according to the different stimulation and intermittent times, as well as the distinct impacts on cortical excitability, TBS can be categorized into intermittent TBS (iTBS), which facilitates excitatory outcomes, and continuous TBS, which results in inhibitory effects. It has been found that rTMS in the TBS mode is effective and safe for the treatment of anxiety, depression, and hallucinations[10]. However, there are no reports on the use of non-continuous TBS with rTMS for the treatment of patients with AD experiencing depressive symptoms. Based on this, the present study selected 105 patients with AD and depressive symptoms as research participants, aiming to investigate the application effect of the non-continuous theta short-burst rapid pulse mode of rTMS, with a view of providing a reference for the popularization of the application of the TBS mode.

MATERIALS AND METHODS

General information

The clinical data of 105 patients with AD accompanied by depressive symptoms admitted to the Huzhou Third Municipal Hospital, The Affiliated Hospital of Huzhou University, between January 2020 and December 2023, were selected and divided into control group (n = 53) and observation group (n = 52) according to the different treatment modalities.

Inclusion criteria: (1) Participants must meet the clinical diagnostic criteria of AD[11] and the diagnostic criteria of depression, specifically AD combined with depressive symptoms; (2) Cranial magnetic resonance imaging or computed tomography suggesting diffuse cerebral cortical atrophy; (3) Mini-mental state examination (MMSE) scores for illiterate people ≤ 17 points, primary school group ≤ 20 points, secondary school and above group ≤ 24 points; (4) Cornell scale for depression in dementia score ≥ 8 points; (5) No history of epilepsy or other psychiatric disorders; (6) Aged 55-85 years old; (7) Absence of other systemic and organ pathologies; (8) Normal literacy; and (9) Stable vital signs.

Exclusion criteria: (1) Those who were receiving treatment related to this disease; (2) Those who were depressed due to other diseases or emotional factors; (3) Those who had other combinations that may cause cognitive dysfunction; (4) Those who had severe cardiovascular and cerebrovascular diseases or hepatic and renal insufficiency; (5) Those who had severe dementia; (6) Those who had unauthorized use of other treatment protocols related to this disease during the course of treatment; and (7) Those who actively withdrew from treatment.

Treatment method

Both groups of patients were treated with conventional medication, and the observation group received treatment with the non-sustained theta short-burst rapid pulse mode of rTMS. A rTMS therapeutic instrument was used, with the frequency set at 1 Hz and the stimulation intensity at 80% of the motor threshold (MT). The main stimulation site was the dorsolateral prefrontal cortex (DLPFC) of the bilateral frontal lobes. A quiet treatment place was chosen, maintaining the room temperature at 16-23 °C. Patients assumed a flat or lateral position, with the treatment coil centered in the temporal cortex. It was adjusted to the non-sustained TBS mode for treatment, with the stimulation site and volume adjusted according to the amplitude of the waveform of the action evoked potentials during treatment. The first-day parameter was 80% MT, and on the next day, it was 100% MT. The stimulation site was the left DLPFC. The inter-cluster frequency was 5 Hz, the series stimulation time was 2 s, the series interval time was 8 s, the number of pulses in the cluster was 3, and the intra-cluster frequency was 50 Hz. The total number of pulses administered was 600, totaling 3 min and 12 s per session, conducted twice a day. During treatment, both the patients and operators wore earplugs. Each course of treatment lasted for 5 days, with a 1-day interval between each course, totaling two courses of treatment.

The control group received pseudostimulation treatment, and the implementation of the treatment protocol was consistent with that of the observation group. During the treatment, the stimulation magnetic head was turned 180°.

Observation indicators

The Observation indicators are as follows: (1) The self-rating depression scale (SDS) was used to assess the depressed mood of both groups of patients on the day of admission (T0) and 15 days after treatment (T1). A total of 20 items were investigated, and each item was scored on a 4-level scale. A score of ≥ 53 was established as the cut-off value, with higher scores indicating more pronounced symptoms in the patient; (2) The Hamilton depression scale (HAMD) was used to assess the patients’ depressive mood at T0 and T1. The scale consists of 17 items, 10 items scored 0-4 points, 7 items scored 0-2 points, and the total score was 0-54, with < 7 points classified as no symptoms of depression, > 17 points classified as moderate symptoms of depression, and > 24 points classified as severe symptoms of depression[12]; (3) The cognitive functioning of patients at T0 and T1 was assessed using the MMSE, which comprises 7 dimensions covering 30 items, with a score range of 0-30. A score of ≥ 27 suggests normal cognitive functioning, with higher scores indicating better cognitive performance[13]; (4) Clinical efficacy was determined by evaluating the change in HAMD-14 score, the HAMD scale score reduction rate was calculated as [(T0 score - T1 score)/T0 score] × 100% - cured: Score reduction rate > 75%; Apparent effect: 50% ≤ score reduction rate ≤ 75%; Effective: 25% ≤ score reduction rate < 50%; and Ineffective: Score reduction rate < 25%; and (5) Adverse reactions during treatment, including tingling sensation, panic, and headache, were recorded in both groups.

Statistical analysis

Statistical analysis was performed using Statistical Product and Service Solutions version 20.0. Continuous data were represented as mean ± SD with a t-test; discrete data were presented as frequencies and percentages [n (%)] and compared using the χ² test. Statistical significance was set at P < 0.05.

RESULTS

Comparison of general data between two groups of patients

There were no differences in sex, age, disease duration, or education level between the two groups of patients included in the statistical analysis (P = 0.496; P = 0.210; P = 0.576; and P = 0.868, respectively), as shown in Table 1.

Table 1 Comparison of general information of patients in the two groups, n (%).

Groups	Sex		Age (mean ± SD, years)	Course (mean ± SD, year)	Standard of culture
	Males	Females			Primary and below	Middle school	College and above
Control group (n = 53)	29 (54.72)	24 (45.28)	72.26 ± 6.17	5.26 ± 1.02	12 (22.64)	18 (33.96)	23 (43.40)
Observation group (n = 52)	25 (48.08)	27 (51.92)	73.85 ± 6.52	5.15 ± 1.10	10 (19.23)	17 (32.69)	25 (48.08)
χ2/t	0.463		-1.261	0.561	0.284
P value	0.496		0.210	0.576	0.868

Depressive symptom scores

At T1, both groups exhibited a marked reduction in SDS and HAMD scores compared to at T0 (P < 0.05), with the observation group showing a more pronounced decrease than the control group (P < 0.05, Figure 1).

Figure 1 Depression symptom score. A: Self-rating depression scale; B: Hamilton depression rating scale. ^aP < 0.05. SDS: Self-rating depression scale; HAMD: Hamilton depression rating scale; T0: Initiation of hospitalization; T1: 15 days post-treatment.

MMSE score

After receiving different therapeutic measures, by the time of the T1, the MMSE scores for both groups had shown a pivotal increase from T0 (P < 0.05). Furthermore, the observation group had a greater degree of improvement than the control group (P < 0.05, Figure 2).

Figure 2 Mini-mental state examination score. ^aP < 0.05. MMSE: Mini-mental state examination; T0: Initiation of hospitalization; T1: 15 days post-treatment.

Clinical efficacy

In the control group, 14 patients had ineffective treatment effects, whereas in the observation group, the number was reduced to 5. The number of cases displaying ineffective treatment outcomes in the observation group was notably fewer compared to the control group (P < 0.05), as shown in Table 2.

Table 2 Comparison of clinical efficacy results in the two patient groups, n (%).

Groups	Recovery	Effectual	In force	Null and void	Overall effectiveness
Control group (n = 53)	7 (13.21)	13 (24.52)	19 (35.85)	14 (26.42)	39 (73.58)
Observation group (n = 52)	10 (19.23)	17 (32.69)	20 (38.46)	5 (9.62)	47 (90.38)
χ2					4.998
P value					0.025

Adverse reactions

The variation in the occurrence of adverse reactions was comparably minimal across both groups under investigation (χ² = 0.485, P = 0.486), as shown in Table 3.

Table 3 Comparison of adverse reactions between the two groups, n (%).

Groups	Tingling	Burning pain	Palpitation	Headache	Footing
Control group (n = 53)	1 (1.89)	2 (3.77)	1 (1.89)	0 (0.00)	4 (7.55)
Observation group (n = 52)	2 (3.85)	1 (1.92)	1 (1.92)	2 (3.85)	6 (11.54)

DISCUSSION

AD is one of the most common diseases leading to the loss of daily living ability in the elderly. It is characterized by full-blown dementia, manifesting as personality and behavioral changes and a persistent decline in intellectual cognition. Currently, it is clinically incurable[14,15]. According to a survey, the prevalence of AD in China is approximately 3.94%, with the number of patients reaching 9.83 million. AD imposes a serious disease burden, bringing heavy medical, care, and economic burdens to families and society[16]. AD and depression share some common pathological characteristics[17], prompting researchers to focus on their co-occurrence and the development of depressive symptoms as the main risk factors[18]. Surveys have shown that approximately 50% of patients with AD have anxiety and depression with cognitive and behavioral changes, which can exacerbate the AD condition and affect the treatment of AD to a certain extent[19]. The high morbidity and disability rates of AD have made it a major public health problem and a growing social and family burden and medical problem worldwide, and the prevention and treatment of AD have become a major issue in modern medicine.

Previous studies have found that rTMS induces brain functional remodeling through magnetic field-induced currents, improves brain metabolism and synaptic plasticity, regulates interconnections between neurons, and effectively alters cerebral cortical excitability. These changes improve cognitive function and psycho-behavioral symptoms in patients with AD, thus providing new hope for the rehabilitation treatment of AD[20,21]; however, the specific mechanism of its action is not yet completely clear and lacks profound theoretical support. Non-sustained theta short burst rapid pulse mode, also known as intermittent theta rhythm stimulation, is a newly developed high-frequency treatment mode in recent years. It is a clumped stimulation modality simulating the physiological action potential burst discharge in the human hippocampus, and it has good effects on depressive symptoms. Additionally, it features low treatment time and high efficiency[22]. In this study, we showed that, at T1, the HAMD and SDS scores of the observation group were significantly lower than those at T0, indicating that the TBS treatment mode of rTMS has good clinical efficacy for depressive symptoms in patients with AD. This may be related to rTMS promoting the repair of newborn nerve fibers, improving nerve conduction, and regulating norepinephrine expression.

The mechanisms by which depression affects cognitive function in patients with AD are not clearly established and still need to be further explored. Chen et al[23] conducted a meta-analysis that found depression to be associated with frontal-limbic circuits, with the prefrontal cortex identified as the command-and-control center of the brain, reflecting higher executive functions, cognitive-functional behaviors, and attention. Therefore, the effect of depressive symptoms on cognitive function in patients with AD may be related to the prefrontal cortex. In this study, iTBS with rTMS for patients with AD with comorbid depression showed that the improvement in MMSE scores in the observation group was better than those in the control group, suggesting improved cognitive function among patient pairs, similar to the study by Wu et al[24]. As the pathogenesis of AD is more complex and closely related to the damage to the patient’s cerebral cortex or hippocampal functional areas, brain tissue metabolic abnormalities, and neurotransmitter disorders, the reduction of acetylcholinergic neurons and the decrease in transmitter levels can lead to impaired cognitive function[25]. We speculate that the TBS mode of rTMS may produce excitatory euthanasia in the prefrontal cortex, accelerating cerebral metabolic activity, promoting interaction between the cerebral cortex and subnuclei, and improving the function and structure of neural cells. These effects may improve the cognitive function of the patients and alleviate the symptoms of AD. Moreover, rTMS can directly stimulate the cerebral cortex, hippocampus, and striatum, which can effectively regulate cerebral microcellularity and improve metabolism. Furthermore, it promotes the release of neurotransmitters such as acetylcholine to a certain extent; this can significantly increase the content of acetylcholine in the brain tissue of patients, thereby enhancing the function of cholinergic neurons and improving the symptoms of cognitive impairment.

In addition, Lowe et al[26] compared the effects of continuous theta rhythm stimulation of rTMS with those of standard rTMS and found that the pulses delivered through the scalp interacted with neural firing. They concluded that iTBS was more in line with the rhythmic firing pattern of the brain itself. Some studies have pointed out that rTMS has better applications in the treatment of AD, depression, and stroke and is considered satisfactory for addressing various neurological disorders[27]. In this study, the observation group demonstrated a more effective treatment success rate than the control group, with no serious adverse events recorded in either group, indicating that the iTBS mode of rTMS is effective, safe, and reliable in the treatment of AD with depression. However, this study is a single-center study, and the sample size is small; hence, the results of the study have certain limitations. Therefore, it is necessary to carry out large-sample, multi-center, long-term follow-up clinical trials in the future to further explore the mechanism of iTBS mode of rTMS in the treatment of AD with depressive symptoms so as to provide stronger support for clinical practice and patient treatment.

CONCLUSION

The treatment of AD with depressive symptoms using the iTBS mode of rTMS has obvious advantages in improving depressive symptoms, mental status, and quality of life, thus enhancing the overall effectiveness of rTMS treatment, this is worthy of promotion and application.